Is S a r c o i d o s i s a n A u t o i m m u n e D i s e a s e ? : R e p o r t o f Four C a s e s and R e v i e w o f the L i t e r a t u r e By Craig W. Wiesenhutter and Om P. Sharma

A

RELATIONSHIP between autoimmune disorders and sarco~dosis has been previously proposed. In 1946, Teilum *~ noted certain similarities between connective tissue diseases and sarcoidosis and recmphasizing these findings in ! 964, "7 he postulated that sarcoidosis ~nd connective tissue diseases shared a common immunopathogenic mechanism. However, reports of sarcoidosis coexisting with connective tissue diseases are rare. An extensive review of the literature disclosed one previously reported ease of sarcoidosis coexisting with progressive systemic sclerosis (PSS) 9 and two cases of sarcoidosis coexisting with systemic lupus erythematosus (SLE). H6"I'9The discovery of an additional four cases of sarcoidosis occurring in combination with uncommon connective tissue diseases prompted a review of the literature for evidence suggesting a relationship between sarcoidosis and autoimmune disorders. CASE REPORTS

Case i A 20-yr-old black female was admitted to the Los Angeles County--University of Southern California Medical Center on May 25. 1972, with a 3-day history of fever, chills, and a bluish discoloration of her fingertips associated with pain on exposure to cold. Prior to this admission, the patient had been in excellenl health. On physical examination, Ihe pertinenl findings included a temperature of 100.2°F. She was found to have submandibular lymphadenopathy, and a spleen tip was palpable 2 cm below the left costal margin. On exposure Io cold, she developed cyanmis of her fingertips. The remainder of the physical examination was within normal limits. Laboratory data showed a hematocrit of 24%, white blood count of 6000 cm ~, with 62% polymorphonuclear leukocytes, 27% lymphocytes, 8% monocytes, and 3% cosinophils, platelet count 70.000 cro). reticulocytes count 77o. cr~lininc 2.7 mg/lO0 ml. serum urea nitrogen 35 mg/lO0 ml. gluc~e

From the Pulmonary Disease Service and Department of Internal Medicine. Lax Angeles County-University of Southern California Medical Center. 1200 North State Street. Los

Angeles. Calif. Addre~ for reprint requests" Om P. Sharma. MAY, A~ociate Profe~xor of Medicine. Pulmonary DiJease Service. Los Angeles County-UniverMty of Southern .California Medical Center. 1200 North State Street, Los An&ele& Calif.90033. © 1979 by Grune & Strotton. Inc. oo4 9-o17 21791ooo2-ooo Jso 5.oo/o 124

160 mg/lO0 ml, calcium 9.8 mg/lO0 ml, haptoglobin 4 mg/lO0 ml (normal, 20-204 mg/lO0 ml), direct Coum,bspositive, Is(; 3.3 8m/lO0 ml (normal 0.7-1.7 gm/lO0 ml), nntinuclear antibody I:160, C3 32 mg/ml (normal 58-103 mg/ml), lupus crylhcmalnsUS preparation nonreactive., and hepatitis B surface antigen nonreactive.Urinalysis showeda 4+ protein and 44- blood on dip stix. There were 75-80 white blood cells and 30-40 red blood cells per high power field with numero~ red blood cell casts. A 24-hr urine protein was 5.9 g. A chest x-ray was within normal limits. The patient was diagnosed as having SLE complicated by hemolytic anemia, thrombocytopenia, and nephritis. She was started on prednisone 60 mg daily and cyclopl~phamide, 50 m8 daily, in the outpatient department, her prednisone was tapered over an 8-me period. The cyciophusphamide was discontinued on the patient's own accord I yr following di.u:harge. The patient did reasonably well, being bothered only by intermittent arthralgias, until June 1974, when she returned to the clinic complaining of nervousness, insomnia, and heat intolerance. On physical examination, she was found to have exophthalmos and a lid lag. A fine tremor was noted and 4 + deep tendon reflexes were elicited throughout. Thyroid function studies showed a thyroxine by MurphyPatten T,(D) of i?.7 ~g/100 ml (normal. 4.6-10~g/100 ml as thyroxine), resintriiodothyroninc uptake (RTjU) 14.4% (normal, 10.0%--14.6%), long-acting thyroid stimulator (LATS) nondelcctable, and antithyroglobulin liter 1:128 (normal, lem than 1".32). The patient was started on methi. mazol¢ 60 mg daily. Three months later, I me after di.u:ontinuing the methimazole, the patient was" reevaluated and appeared to be clinically euthyroid. Thyroid function studies at that time were T, (D) of 1.7 ;,g/100 ml and RT3U 8.6%. Over the ensuing year renal function progressively deteriorated, and she was rehospitalized in June 1975. Physical examination showed diffuse thyroidmegaly and a right elbow effusion without deformity or restriction of motion. There was no detectable organomegaly or iymphadcnopathy. Labor a l o r y data showed a serum ereatinine of 6 rag/100 ml, serum urea nitrogen 60 rag/100 ml, and an antinuclear antibody liter greater than 1:160. The chesl x-ray demonslrated cardiomegaly without parenchymal .h~filtrates or hilar adenopathy. Following dischargc, the patient was started on chronic hemodialysis. She did reasonably well until January 1977, when she had the on.~t of recurrent fevers with temperature spikes to 105OF unamo~ted with chills or diaphoresh. In June 1977, the patient was rchmpitalized. Physical examination showed a temperature of 1020F. She appeared to be in no acute dbtreut. Difftm: thyroldomegaly was still present. The lungs were clear to percussion and amcdltation. A smooth nontender liver edge was palpable 3 cm below the right mid-costal margin. A spleen tip was palpable below the left cmtal margin. Laboratory data showed a hematoerit of 19%, white blood count of 4 2 0 0 ~ with 59% l~lymorphonuclear lcukocytes, 24% lym~hocyt¢~ 10% monocTte~ $% eeeinophilz, and 2% ba.mphil~ platclet count normal, creatininn 15.3 rag/100 ml, ~ m urea nitrogen 67 rag/100 ml,

S~l/m~/nArz~r/~ a n d S ,

Vol. 9, No. 2 (November), 1979

125

SARCO~OStS

antinuclear antibody tiler 1:8, direct Cnombs weakly positive, angiotensin-l-convertingenzyme 4 2 | U/I (normal i 030 IU/I for femal,'*) T, by radioimmunmssay 4.8g/100 mi (normal 4.2-15 g/IDO ml, RT~U 0.75% (normal 0.8595-1.1%), Tj by radioimmunoax~y 157 rig/100 ml (normal 70--179 ng/IDO ml), and free 1"4 index (T~-RT~ index) 3.6 (normal 2-15). The chest x-ray showed ¢ardiomegaly.Liver biopsy a~d bone marrow biopsy specimensshowed numerous noncaseating granulomas, (~fft. I and 2). Cultures and spec/al stains for fungi and tuberculosiswere negative and a diagnosisof sarcoidosiswas made. The patient was started on prednisonewith subsequentmarked clinical improvement. COMMENT

T h e patient meets five criteria from the A m c P ican R h e u m a t i s m Association for the classification of S L E ( R a y n a u d phenomenon, arthritis without deformity, profuse proteinuria, cellular casts, and hemolytic a n e m i a ) and, in addition, has supporting serologic studies. T h e criteria for establishing the diagnosis of sarcoidosis, such as a compatible clinical picture, histologic evidence o f noncaseating g r a n u l o m a t a , a n d negative cultures, are also met. In this case, the connective tissue disease preceded by several years the onset of clinically overt sarcoidosis. In regard to her thyroid disease, it is not clear whether she had Graves disease that spontaneously resolved, or Hasl~imoto thyroiditis.

Case 2 A 47-yr-old, white male was in good health until 1967. when he attempted to donate blood4,mrwas refused because

160)

of anemia, lie was then evaluated at an outside hospital. Physical examination at that time was within normal limits~' but a chest x-ray showed bibasilar interstitial infiltrates. A

scalene node biopsy was performed that showed numerous noncascating granuloma (Fig. :3). Stains and cultures .for fungi and tuberculosis were negative and a diagnosis of sarcoidosis was made. Subsequently, he was followed by private physiciansand in 1969 developed a skin rash involving his lateralflank~anterior trunk, and ,~tten~ surface of his arms. A diagnosis of dermatitis herpetiformis, oonfirny;d by skin bio~y, was made., and hc was starte~l on treatment

with sulfnpyrkii~e. Also at that time., his fingers and toes became cyanotic while being examined in a cool room. They returned to normal foJlow)ngwarming. Upon questioning,he admht.ed to a iO yT h~(o~ of developinga numbing pain with a bh,'ishdiscolorationof his fingersand toes on exposure to cold. Over.the ensuing 3 yr he noted the gradual onset of 4-5 block dyspnea on exertion and in 1971 he developed ankle edema. Hc was referredto the Los AngelesCounty-University0tSouthern California MedicalCareer and w u hospitalized ~n October 1972. ,At that time, he complainedof some .difficultyin openinghis mouth widelyand of some tightening of t11¢skin around his hands.

On physical examination, the patient appeared thin with "pinched facies." Examinationof the skin showed a maculopapular rash with hYlgrpigmenlalion over the right flank. Auscultation of the lungs showed dccgcasod breath sounds diffusely. Epitro~lear lymph nodes were noted bilaterally. The liver edge was palpable 3 cm below the right mid-cmlal margin. On examinationof the extremities, 1+ ankle edema was noted. There was acrocyanmis of the fingers and toes and thickening of the skin on the hands with loss of the wrinkles over|yingthe prnx]malinterphalangcaljoints. Laboratory data showed a hematocrit of 35%. white blood count of i i,900/cm', with a normal different/al, cafc/um 10.5 mg/lO0 rot. gamnm globulin 2.2 B/! DO ml with a broad

126

VV]ESENHUTTER .AND SHARMA

Fig, 2. Case 1 : A bone marrow l~iops¥ showing many noncaaeating granu|oma~. (H.E. X 100)

Fig. 3. Case 2: A scalene node b}opty ~ ~ numerous noncaseating granuJomaa (H.E. x 55)

SARCOIDOSIS

127

band (normal 0.5-1.5 g/100 ml), angintensin-l-converting enzyme 30 IU/I (normal 12-31 IU/I in males), antinuclear antibody titer 1:160, lupus erythemat0sus cell preparation positive, and qualitative cryoglobulins positive. Arterial blood gases on room airrevealed an oxygen tension of 60 ton, carbon dioxide tension 37 tort, pH 7.48, and bicarbonate 28 mmole/I. A 5 TU pu~ofied protein derivative skin test was negative. Serum electrolytes, uric acid, cholesterol, and liver function studies were within normal limits. A chest x-ray showed cardiomegaly a~d a diffuse interstitial infiltrate with hor,ey-combing at boih bases (Fig. 4). An upper gastrointestinal series with cme~esophogram was wtthm normal limits. Pe6pheral lymph ~ode and bone marrow biopsies were unremarkable. A liv'er biopsy showed mild central lobular necrosis. \ The patient was felt to have c h romc,'inactive, sarcoldosis and progr~,.sive systemic sclerosis, together with mild congestive heart failure. He was started on prednisone 40 mg daily, digoxin, and a diuretic. He was followed in the outpatient department and did well with no further deterioration of his exercise tolerance. However, over a period of several years, he had progressive tightening of the skin around his hands, and in 1977 he began complaining of dysphagi~. Over the next 6 mo, he lost 35 Ib in weight and in September 1977, he was rehospitalized. On physical examination, he appeared cachectic, but was in no acute distress. Several telangectasias were noted around the mouth and on the nose. There was marked acrocyanosis and the skin on the hands was taut. There was no thyroidomegaly. Laboratory data showed a hematocrit of 32%, antinuclear antibody titer of 1:32 with a peripheral pattern, latex fixation was reactive to 1:320, extractable nuclear antigen negative, lupus erythematosus preparation negative. "1"4by radioimmunoassay 3.2/ag/100 ml (normal 4.2-15 ,ug/100 ml). RTjU 1.34% (normal 0.85-1.1%), T~ by •

•

\

.

.

\

.

radioimmunoassay of less then 25 ng/100 ml (normal 70170 ng/100 ml), T(RT, inde= 4.3 (normal 4.2-15), and thyroid stimulating hormone of 11.7 taU/ml (normal 0-5 ~U/ml). An upper gastrointestinal series with cine-esophagram showed diminished esophageal motility. X-rays of the hands showed periarticular dimineralization. With encouragement and the use of a soft diet, he increased his caloric intake and started to gain weight. Since discharge he has done reasonably well. COMMENT

.

In this c a s e , s a r c o i d o s i s p r e c e d e d t h e i n s i d i o u s o n s e t o f P S S . T h o u g h clinically e u t h y r o i d , t h e thyroid functions studies are compatible with a loss o f t h y r o i d reserve. T h e d e v e l o p m e n t o f d e r m a t i t i s h e r p e t i f o r m i s is i n t e r e s t i n g in t h a t t h e s e lesions m o s t likely r e p r e s e n t i m m u n e c o m p l e x m e d i a t e d tissue d e s t r u c t i o n a t t h e dermoepidermal junction? 7

Case 3 A 48-yr-old black female was admitted to the Los Angeles County-University of.Southern California Medical Center in December 1961 with a 6-mo history of weakness, myalgias, and migratory arthralgias. Four months prior to admission, she noted blurring of her vision. She was evaluated by an ophthalmologist who diagnosed granulomatous unveitis. A chest x-ray film showed right paratracheal and bilateral hilar adenopathy (Fig. 5). She has been followed at the medical center since 1925 and during several previous hospital admissions for surgical procedures, numerous chest x-ray films were within normal limits. The family history is significant in

•

b+ % :

F'~. 4. C a w 2: A postero-antarior chest-roentganogram ¢~owin~ diff~a interrlili~l lung infiltrate and honey-

combing.

"

VC 27 72 12

5

32 69

,: ~ ~:,'.,. :-~

:,

Fi~. 5. Case 3: A poitaro-lmtarior view of chest roerrt+ g e n o g r a r n - I h O w ~ bilateral hilar adenopathy and right parlrtrache~ll adenopathy.

VVIESENHUTrER AND SHARMA

128

that onc of her daughters was diagnosed as having S L E at the age of 29 and another daughter was diagnosed as having rheumatoid arthritis at 7 )'1"of age. The physical examination was unremarkable except for multiple abdominal scars. Laboratory data showed a hemoglobin of 12.7 g / ! 0 0 ml, while blood count of 4,400 cm j. with 65% polymorphonuclear Icukoc)les, 27% lymphocytes, 2% monocytes, and 6% ¢osinophils, calcium 9.4 mg/100 ml, albumin 4.0 g/100 ml, globulin 3.9 g/100 ml, gamma globulin 1.9 g/100 ml (normal 0.5--I .5 g/100 ml), lupus erythematosus c¢11preparation negative, cryoglobulins and cold agglutinins nondctcctabl¢, and latex fixation weakly positive. Serum electrolytes, urinalysis, and electrocardiogram were within normal limits. A scalene node biopsy was performed that showed numerous noncascating granulomas. Stains and cuhuros for fungi and tuberculosis were negative and a diagnosis of sarcoidosis was made. The patient was discharged on prednisone symptomatically improved. Following discharge, she did well but continued to complain of painful joints, primarily in the hands and wrists. in i 962, she began to notice a dusky discoloration and aching in hcr fingertips on exposure to cold, which persisted. At approximately the same time, she developed multiple ulceralions of her fingertips which, after a short period of time. spontaneously resolved. Scvcn years later, she had the onset for the first time of dyspnea on exertion, which progressively incrcased in scverlty, and she developed a productive cough. She was rehospitalized in December. 1969. On physical examination, some thickening of the skin on the hands was noted. On exposure to cold water, she developed pain and cyanosis of the fingertips. The chest x-ray film showed right paratrachcal and bilateral hilar adc~opathy with a diffuse interstitial infiltrate. X-ray films of the hands showed multipie soft tissue calcifications involving the distal a~.pcct of the first and second digits of the right hand (Fig. 6). A high speed drill percutancous lung biopsy was performed that showed numerous noncascating granulomas and active destruction of parcnchyma with an associated chronic

inflammatory cell response and focal aggregates of degcneratingcollagen (Fig. 7). At thistime, prednisone was increased from I0 m g daily to 40 m g daily. Her exercise tolerance has stabilized.However. she continues to complain of Raynaud phenomenon, a productive cough, and joint pains, especially involving the first and second digits of her right hand. O n physical examination. there has bccn somc further tightening of the skin ~round her hands and lossof wrinkles overlying her proximal interphalangcal joints and on her face. In October 1973, an upper gastrointestinalseries with a cinc-esophogram showed a dilated esophagus with an absence of primary waves (Fig. 8). Multiple antinuclear ~mibodies, extractable nuclear antigcns. and lupus crylhematosus preparations have been negative.The paticnt is believed to have ~ .rcoidosisand PSS. COMMENT

in this case also, sarcoidosis prcccdcd the development of a connective tissue disease. As in the second case, Raynaud phenomenon documented the onset of PSS several years before the diagnosis became apparent. The positive family history for connective tissue disease is noteworthy. Case 4 A 46-year old Caucasian female was admitted to the White Mcmorial Medical Center hospital in February 1978 with a three-week history of dimculty swallowing associated with a retrosternal pressure scnsotion, nausea, and vomiting. She first presented to the White Memorial Medical Clinics in November 1977 complaining of l~inful, discolored fingertips when they wcrc exposed to cold. and pain and swelling of h~r knees and metacarpal phalangeal joints bilaterally. A chest x-ray showed bilateral hilar adenopathy

F'q]. 6. Case 3: X-fay f i l m of the hands showing mzdtiple soft tissue calcificatiorm im~lvlng the distal aspect o~t M ~r~t ~ hand.

~

cr~gltsof the right

129

SARCOIDOSIS

Fig. 7. Case 3: A high speed drill percutaneous lung biopsy showing many noncaseating granulomatn. IH.E. X 120)

and fight paratmcheal lymphadenopathy. She was immediately admitted to the hospital and underwent mediastinoscopy and lymph node biopsy. This showed numerous noncaseating granuioma. She was discharged with a diagnosis of pulmonary sarcoidosis, Raynaud phenomenon and arthritl¢. •On this admission, the physical findings were within normal limits, except for the hands, which showed diffusely hyperemic, swollen digits. Laboratory data, including chemistries, complete blood ¢cll count, and urinalysis were within

normal limits. An ¢sophagram showed a large hiatal herni~ and early stricture formation of the distal esophagus. Esophagogastroscopyw a s performed that showed apefistalsis and incomiglencc of the lower esophageal sphincter with ulceration and mild stricture formation of the distal esophagus. Bilateral hilar adenopathy and right par~tracheal lymphadenopathy by x-ray remained. She was discharged with a diagnosis of sarcoidc~is and PSS with Raynaud phenomenonand esophageal involvement..

COMMENT In ~ill three case.s in which PSS coexisted with sarcoidosis, PSS b e c a m e manifest with symptoms of R a y n a u d phenomenon, sclerodermatous changes of the hands, and visceral involvement that consisted of disease o f the distal esophagus. Unlike the other two cases, in this patient the diagnosis of saroaidosis and PSS were made at approximately the same time.

DISCUSSION sarcoidosis is a multisystem granulomatous discas~ that most commonly affects the hilar lymph nodes, lung parenchyma, skin, and eyes, though nearly any organ or tissue type can be involved. '37 Histologically, the basic lesion is'a well-defined round Or oval granuloma made up

F'~I. 8..'. Case 3" An uppergaltrolnte*tlnal study demonrotating mo"dm'~lmm~lmgua.

of compact radially arranged epitheloid cells, a few multinucleatc giant cells, and a scanty rim o f lymphocytes. Caseation is absent, though small areas o f fibrinoid necrosis m a y be noted. T h e criteria for establishing the d i a g n ~ i s o f s a r c o i d osis i n c l u d e : ( A ) : compatible clinical a n d ] o r

~NIESENHUTI'ER AND SHARMA

130

radiologic findings; (B) histologic evidence of noncaseating granuloma; and (C) negative cultures and the absence of other agents that can cause epi!heloid-granuloma. The etiology and pathogenesis of sarcoidesis remains unknown. The possibility that sarcoidosis may represent a hypersensitivity response to a single or multiple inciting agents has been considered.. The immunologic features and abnormalities of this disease have been receiving increasing attention. A depression of ceil-mediated immune function in association with hyperactivity of the humoral immune systerfi can .be demonstrated in sarcoidosis.. The apparent simi.~,lrity of this immunologic profile to the abnormalities found in animal models of autoimmunity and human SLE raises the possibility that similar immunoregulatory defects exist between these disease states. The recent data pertaining to immunoregulation and the role of immunoregulatory defects in the pathogenesis of disease in animal nodels and humans will be reviewed briefly. The Lbnormalities and features of the immunologic derangement in SLE, PSS, and sarcoidosis will be compared in greater detail, and the available evidence to support a relationship between sarcoidosis and autoimmune disorders will be presented. The possible therapeutic implications for these findings will also be discussed.

IMMUNOREGULATiON AND REGULATORY CELLS

and production of antibody against the hapten. The message by the helper T-cell is delivered by humoral factors,'9"lu''ss which have been .shown to stimulate B-cell responsiveness to specific antigens or to stimulate a heterogeneous popuiation of B-cells capable of respondingto a variety of antigens. Direct contact has not been shown to be required for these interactions to take place. T-cells are also concerned with helper function in cell-mediated reactions. 2~'t60 Suppressor T-Cells The negative regulatory component of the immune system is represented ,by negative feedback b y antibodies) 62 In addition, a series of suppressor cells modulate the system, the most prominent role being played by the suppressor T-cell. t~'6~ There is good evidence to suggest that suppressor T-cells are a group distinct from helper T-cells in humans) ~7 Several soluble Tcell suppressor factors have now 'been demonstrated and have been shown•to be both antigen specific and nonspecific. .6~ The target cells for these suppressor factors include other •T-cells, ss mact'ophages,' and though not conclusively proven, B-cells. ~ Suppressor cell fimction has been shown to play a n active role in an array of humoral and cell:mediated immune• phen0menal '~'16~ In •addition, suppressor. T-cell defects have been increasingly implicated .in several animal a n d human diseases, including the autoimmune disease of the New Zealand mice. human SLE and other.•human, autoimmune ' diseases: A t the other end of the spectrum, hyperactive Suppressor T-cells have been implicated in causing the disease manifestations of at least some patients with human agammaglobulihernia and selective deficiency of IgA, ~6~

•A complexed system of beth Positive and negative regulatory factors are responsible for generating and maintaining an optimum immune response. The three major cell types tha't take part in these interactions are T lymphocytes (T-cells), B.lymphocytes (B-eel!s), and macrophages. Recent work has shown that these major Macrophages ..- :::. •groups can be divided into functional subclasses. There arc several reviews that deal.with this-i Besides its well-known function as a phagotopic in greater dctail,SSg"!~"6~ . cyte)~ the macrophage also plays a prominent • ~• ' " role. in .immunoregulation~ The presence .: of Helper T - C e l l s . . • " macr0phages is required for T-cell:aetiva•The humoral response by B-ceils io a variety. • tion s69xl and,in some systems, for a maximal of antigens requiresthe cooperation of T'celis. zg. :humoral response)63.~ Unlike T-cell-B-cell and The T-cell's function in this :interaction is t o T-cell-T-cell interactions, direct eell-to-cell"con-. identify the larger carrier moleculeto which.the " tact is easy todem0nstrate between the macro- . antigen is connectedand then to relay a message. • phage and T-cells. These coniact s'are- imPortant t o t h e B-cell attached to thehaptenic-determi• in the developmc~nt o f theimmunc response.9Tats " nant. This results in the activation o[ th e B-cell:. Also, some evidence=suggests that macr0phages •

•

'

•

•

•

"

"

i

'

"

131

SARCOIDOSIS

interact directly with B-cells to promote a maximal humorai response. 2a Direct contact is not prerequisite for macrophage helper function to take place, however, and soluble factors that enhance immune responses have been demonstratodY .s8 Macrophages also mediate negative regulatory responses for they have been shown to inhibit mitogen and antigen induced immunologic reactions, sS".~+ Soluble suppressor factors derived from macrophages have been isolated,j~ Macrophage suppression has been implicated in human disease, such as the immunodeficiency associated with multiple myeloma"~ and the anergy of Hodgkin's disease. Disordered immunoregulation has been best studied in the animal model, New Zealand mice, which in many ways mimics human SLE. ANIMAL MODEL OF AUTOIMMUI~IITY: THE flEW ZEALAND MICE

New Zealand Black (NZB) and NewZealand Black]New Zealand White (NZB/NZW) F) hybrid mice develop a spontaneous, relentlessly progressing autoimmune disorder characterized by the presence of diverse autoantibodies, immune complex giomerulonephritis, monoclonal macroglohulinemia, defective T-cell function, and malignant iymphomasJz'~49-1mThe key features andassociated immunologic deficits in these mice includes:. ( A ) a premature ,development of immunologic competence; (B) at birth, a ,hyperactivity of the humoral immune system reflected by a nonspecific increase in serum immunoglobulins and enhanced humoral response to antigens which decline~ with age; (C) by 2 too, a decrease in suppressor T-cell activity, T-cell tolerance, and serum thymic humoral factors; (D) after 3 mo of age, the development of increasing titers of a variety of auto-antibodies including natural thymocytotoxic antibody; (E) by 5 mo of age, the appearance of hemolytic anemia (in NZB mice); (F) by 6 mo of age, the onset of abnormal parameters of cell-mediated immunitysuch as decreased numbers of circulating T-cells, diminished responsiveness to T-cell mit0gens, and depressed ability to partake of graft-versus-host reactions; (G) after 8 mo of age, the ldevelopment o f lymphoproliferation, monoclonal macroglobulinemia, or, on occasion, frank reticuloendothelial malignancies. . . .

These findings could be explained by a defect in immunoregulation due to a progressive loss of suppressor T-cell function71"t(7"149-~St accounting for the humoral hyperresponsiveness and loss of tolerance to self-antigens. Depressed ceilmediated immunity could be attributed to loss of other subpopulations of T-cells such as effector or amplifier T-~ils. Experimental evidence in support of this view is rapidly mounting. Some examples include that thymectomy in neonatal mice accelerates the autoimmune disease whereas thymectomy in adult mice has no effect. This indicates that suppressor cells, present at birth in these mice, disappear by adulthood. In addition, the transplanting of 2-wk-old thymuses into thymectomized adult mice can reduce the excess antibody responses and inhibit the hemolytic anemia of these adult mice.56'~+v More recently, a loss of suppressor T-cells has been demonstrated in these animals, along with the inability to produce specific T-cell suppressor humoral factors) 9 Of even greater interest, the administration of a soluble immune response suppressor, commencing at an early age, effectively prevented the development of the autoimmune disease, s9 COMPARISON OF 3"HE IMMUNOLOGIC PROFILES OF SLE. PSS. AND SARCOIDOSIS

In general, as with the New Zealand mice, the immune dysfunction of SLE and sarcoidosis consists of B-cell hyperreactivity and depressed T-cell function. Because of the rarity of PSS, experimental data is somewhat lacking. However, available information suggests that these abnormalities are also present in PSS. A detailed comparison of several immunologic parameters between these three diseases is presented in Tables ! and 2.

Hu.moral Immunity The hyperactivity of the humoral immune system in these diseases is reflected by an increase in the three majorS:lasses of serum immunoglobulins in the majority of patients with SLE,43"+J PSS,*~'5! and sarcoidosis, ~6 and by an increase in serum antibodies to a .variety of viruses such as the Ebstein Barr virus and other infectious agents in SLE 73''29 and sarcoidosis.+~a6az7 There is a greater than normal productionof isoagglutinins following an intrave-

VVIESENHU'ITER AND SHARMA

132

Table 1. Humorel Immune System in SLE, PSS, end Sarcoidoeis SUE Serum immunoglobulins Serum antibodies to viruses & other infectious agents Antibody production following challenge with mismatched blood Antibody productior~ following challenge with other antigens NumbeJ" of peripheral B-cell lymphocytes

PSS

5.~coido~

Increased in 6 0 % - 100% during active disease Several increased

Increased in 50%-70%

Increased in 50%-80%

~

Several increased

Increased

Normal

Increased

Normal

Normal

Normal

Increased number of functioning B-cells

Normal

Increased

nous injection of small amounts of mismatched blood in SLE ~7~ and sarcoidosis, m while the elevation in titers equalled controls in PSS. ~ B-ceils are increased in the peripheral 'blood in sarcoidosis, and, though some studies report a decrease in B-cells 'using conventional testing of surface characteristics in SLE, °°'z°s there is a marked increase in functioning B-cells represented by an increase in immunoglobulin synthesizing lymphocytes, lgM-and lgG-producing cells with antibody specificity against DNA and other antigens, and the number of cells capable of binding native DNA, 'TJs The number of Bcells in the peripheral blood is normal in P S S . 39

Cell-Mediated Immunity Cell-mediated immunity is also defective in SLE, PSS, and sarcoidosis. Though there is some conflicting evidence, most st udies demonstrate a decreased reactivity to skin testing with a variety of antigens in SLE, ''69 especially with acute exacerbations of the discaseJ ~ A depression in tuberculin hypersensitivity is evident in all large series of sarcoidosis along witb~:.-y:decreased r e s p o n s e to f u n g a l a n t i g e n s and 2:4

dinitrochlorobenzcnc. 76''42Also, in vitro lymphocyte reactivity to mitogcns is decreased in SLE, 7° PSS, 7°3" and sarcoidosis, 35"~6especially when the patients arc studied during active disease. Peripheral lymphocytes are often decreased in all three diseases. ""'Tn T-cell lymphocytes have been shown to be reduced in the peripheral blood in S L E ) 7.~°'~°s PSS, 39J3° and sarcoidosis, "'66 which appears to be correlated, in most studies, with disease activity. Antibody-dependent cell-mediated cytotoxicity (ADCC) is an example of overlap between the humoral and cell-mediated limbs o f the immune system. Cells that become coated by antibody may be attacked by host effcctor cells that possess Fc receptors. The receptor attaches to the Fc segment of the bound antibody and the effector cell acquires the capacity to kill the target cell./~4 A D C C has been shown to be decreased in S L E j33 and sarcoidosis, s'~ Null cells (cells without T-cell or B-cell surface characteristics) possess Fc receptors and have been considered as one of the effector cells involved with ADCC. -'° There is an increase in the number of null cells in both S L E j7 and sarcoidOSiS. 35.sz

Table 2. Cell-Mediated Immune System in SLE. PSS, and Sarcoldosis SLE Skin Test Response Lymphocytes response to mitogens in ~tro Number of penpher,~/ymphoC~es Number of perq)heral T-cells Nun~be¢ of ~ p h e r a l null cells Anti~ndent cel~t e¢l cytotox~ty (ADCC] Moc~--ytes

PSS

Sa.'c'odo¢~

Decreased. esPecially with active disease Decreased

~

Decreased

Oecrease(~

Decreased

Decreased Decreased Inaeased Impaired

Decleased Decreased ~ --

Decrea.,q~ Decreased Increased Impahred

Hyperbasophilic immunoblasts present in 80%

Hyperbasephilic immuno/blasts peasant in 40%

Activated Mormcujclear c~]ls common

133

SARCOIDOSIS

A utoantibodies

The loss of tolerance to self-antigens is a hallmark of autoimmune diseases. Autoantibodies can also be demonstrated in sarcoidosis. Antinuclear antibodies, found in 95%-100% of patients with SLE ~J and in almost 50% of the patients with PSS, ~z are also present in up to 33% of patients with sarcoidosis, j~'Z~4 Rheumatoid factor is detectable in 20%--40% of patients with $LE, ~= PSS, Jj'74 and sarcoidosis. 7~'~7 While a variety of anticytoplasmic antibodies have been shown to be common in SLE, 35 antimitochondrial antibodies were demonstrated in 25% of patients with sarcoidosis in one series, ads In New Zealand mice, I of the 2 immunopathogenic mechanisms suggested to explain the general decline in T-cell function stems from the presence of natural thymocytotoxic antibody. These antibodies are directed against T-cells and promotes their phagocytosis in vitro. ~39 Their significance in vivo has not been established. It is intriguing, therefore, that antilymphocyte antibodies, most likely directed towards T-cells, have been shown to be present in 70% of patients With S L E TM and in lower titers in 50%of patients with sarcoidosis, 36 while a humoral antilymphocyte factor, that may represent an antibody, has been demonstrated in PSS. t3° " Macrophages

As previously discussed, macrophages play an important role in immunoregulation and may also play a decisive part in the loss of tolerance to self-antigens? 59 Altered circulating monocytes,

the precursors of peripheral macrophages, ~z are found in increa, sing numbers in 80% of patients with SLE and 40% of patients with PSS. 4° The morphologic changes of these cells consist of a high nuclear-to-cytoplasmic ratio. Similar cells are found transiently in viral infections, lasting for 10--15 days, but may be present for long periods of time in connective tissue diseases and seem to be correlated with disease activity. Circulating monocytes in sarcoidosis, with a morghologic resemblance to the altered cells in connective tissue diseases, have been studied and observed to have accelerated phagocytic activity and increased nuclear R N A synthesis and increased ability to bind IgG-antibody-coated and C3-coated erythrocytes, 42 findings consistent with activation. CRYOGLOBULINS, VASCULITIS AND IMMUNE COMPLEX DEPOSITION AND DISEASE (TABLE 3) Cryoglobulins are frequently found in SLE. 9'''46 Their role in the pathogenesis of SLE is not well-understood, but they are correlated with the presence and degree of nephritis. ~7 Cryoglobulins are present in 5 0 % ' o f patients with PSS, 74 and though not often looked for in sarcoidosis, they were detected in one study in 20% of the patients. 25 Serum immune complexes, also correlated with disease activity in SLE, were found in 25% of one series of patients with sarcoidosis 65 and 75% of patients with sarcoidosis and erythema nodosum, s~ lmmunoglobulins and complement

Table 3. Autoantibodies. VascurJtis. and Immune Complexes in SLE, PSS. end Sarcoidosis SLE

PSS

Antinucle~ antibodies Rheumatoid factor Ant ~:ytoplasmic ~untibod~es

Present in 9 5 % - 100% Present in 2 5 % - 4 0 % Present in 5 0 % .

Present in 50% Present in 2 0 % - 4 0 % --

Ant=lymphocyte andbod~e~

Present in 6 0 % - 8 0 %

C~ryoglobulins

Va.c,cufit is

Present in 3 0 % - 8 0 % & correlated with active disease Common

Humocal antiiymphocyte factor present Present in 50%

Saturn immune complexes

Frequently present

TLssue immune cornplexe~

Present

Common. earliest lesion

Print

Sarco;dos~ Present in 5 % - 3 0 % "Present in 2 0 % - 4 0 % Antimitochondrial antibodies present in 25% in one study Present in 3 0 % - 5 0 % Present in ~ 0 %

Presedt in 4 0 % - 7 0 % of open lung biops;es Present in 2 5 % - 7 5 % of patients with e~/thema nodosum Present

134

are frequently demonstrated in the injured tissues in SLE. 96 In PSS, immunoglobulins and complement have been found at the dermocpidermal junction of telangeetasiass and in the glomeruli and intralobular arteries of the kidney, s4 Deposition of immunoglobulins and complement have now been shown in sarcoidosis in and around the granuloma of the lung,~9 lymph nodes, I~° and Kveim reaction, 14j with occasional localization in the vessels. ~3! Quismorio and Sharma ~'s have demonstrated immune complexes in granuloma involving the skin and in the lesions of the Kveim test nodule. McCoy and Tisher, l°= studying six patients with sarcoidosis complicated by nephritis, described glomerular antibody localization similar to any other immune complex mediated glomerulonephritis. In addition, they noted virus-like subendothclial structures in glomeruli akin to those seen in SLE. Vasculitis plays a prominent role as the mediator of tissue damage in SLE s~ and is in all likelihood duc primarily to deposition of immune complexes within the vessel walls. ~ In PSS, the vascular system appears to be one of the earliest organ systems affected with the pathology consisting of myxomatous degeneration and proliferation of small artery endothelial cells and pcrivascular inflammation. '~-~'~7-" The presence of angiitis in sarcoidosis has only sporadically bccn mentioned in the past, but in two recent studies by Rosen et al. '2S and Carrington et al., :~ granulomatous angiitis was found in 40% and 70%, respectively, in open lung biopsy specimens examined from patients with sareoidosis. It was not clear from these studies whether the affected blood vessels were primarily or secondarily involved. However, Rosen el al. did note in their series that two cases with only minimal involvement of the parenehyma with granulomatous disease had inflammcd vessels that were located at some distance from the parcnchymal lesions. They suggested that an independent vascular lesion could occur in some cases of sarcoidosis. Granulomatous angiitis was also described by Licbow~ in a group of ! 1 patients with a disease he termed ,'nccrotizing sarcoid granulomatosis.'" Several features differ from sarcoidosis and these cases probably represent a different disease entity. The presence of cryoglobulins, immune complexes in the serum and tissues, and

WIESENHU3"I'ER AND SHARMA

vasculitis suggests that, as with connective tissue diseases, immune complex mediated disease may a c t as one pathogenic mechanism leading to tissue injury in sarcoidosis. In summary, a comparison of numerous immunologic parameters, measured by currently available techniques, shows a remarkable similarity in the features and abnormalities o f SLE, PSS, and sarcoidosis. These findings can be explained if it is assumed that these diseases share a similar defect in suppressor cell function. PREDISPOSITION TO DEVELOP MALIGNANCY The New Zealand mice, especially the N Z B mice, develop lymphoid hypcrplasia throughout the body. These animals are also predi.~posed to lymphoreticular neoplasms with an incidence as high as 26% being reported. I°~'=°~ An increased incidence of malignancy has also been suggested for SLE 21'9Jand sarcoidosis, '~ and it is of interest that the neoplasms that do develop tend to be derived from lymphoid tissue. The association of malignancy with PSS has been recently reviewed. ' ~ THE ASSOCIATION OF SARCOIDOSIS WITH CONNECTIVE TISSUE DISEASES AND OTHER AUTOIMMUNE DISORDERS It would not be unreasonable to assume that disease states with similar immunorcgulatory disturbances might coexist more frequently than would be expected by chance alone. This assumption might depend on whether the malfunction in immunoregulation was a primary or secondary event. However. if such an association was apparent, it would support the view that similar immunopathogenic mechanisms were involved in these disease states. Connective Tissue Diseases An association between at least some of the connective tissue diseases is obvious. There is a close relationship between SLE and rheumatoid arthritis 4~ and a substantial number of patients presenting initially with rheumatoid arthritis will later develop the manifestations of SLE. A relationship between S L E and PSS also seems

SARCOIDOSIS

likely from the frequency of lupus erythematosus cells in PSS (5%) and the several reported cases of overlap syndromes and patients in whom the two diseases coexist.'3-(4 A relationship between sarcoidosis and connoctive tissue diseases i s far from evident. Though rheumatoid factor is demonstrable in 20%=-40% of patients with sarcoidosis, 75'''7 in one study o.n 94 patients with sarcoidosiso Putkonen and Wager '2( found only one definite and one probable case of rheumatoid arthritis which they felt was no greater than would be anticipated in a normal population. However, at least in certain situations, such as the cystic form of rheumatoid arthritis, the distinction is not clear-cut. '° The protean manifestations of bone and joint involve' ment by sarcoid has been reviewed. 79 The association of sarcoidosis with connective tissue diseases, as previouslymentioned, is rare. However, granulomas have been found in patients with SLE and they were first noted by Teilum. 'Ss He described two women in their early twenties who presented with arthralgias, rashes, albuminuria, and anemia, with one patient having, in addition, leukopcnia, lymphadenopathy, and pleurisy. The patients were diagnosed as having SLE and at autopsy, multipie noncaseating epitheloid-cell granulomas were found in the lungs, blood vessels, and lymph nodes. Similar granulomas were described in a later series of SLE patients by PollackIz3 involving serous membranes and mediastinal and esophageal connective tissues. It is not clear from this report how many patients were represented by these lesions. In a series in which 18 spleens from SLE patients were examined, Dubois (j noted 2 with loosely arranged noncaseating granuloma, and in a series of 7 patients in which palmar tendon sheaths were looked at, a solitary granuloma was detected in one patient. Granulomas have also been described by Shulman et al. =" in tendon sheaths of patients with PSS. It appears, therefore, that granulomas identical to those seen in sarcoidosis do occur on occasion in SLE and PSS. However, an alternative explanation, at least in the two patients described by Teilum, is that these cases represent coexisting sarcoidosis and connective tissue diseases. The frequency of the association of sarcoidosis with connective tissue diseases needs to be reexamined.

135

Other Autoimmune Disorders In a recent review article, Volpe '65 presented evidence in support of his hypothesis that most, if not all, of the organ-specific autoimmune disorders Such as Hashimoto thyroiditis, Graves disease, idiopathic Addison disease, idiopathic hypoparathyroidism, Sjogren syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, etc., are a result of a specific defect in suppressor T-cells. He views this defect as permitting the liberation of a "forbidden" clone of organ-specific self-reactive T-cells, and the activation of B-cells, resulting in both cellmediated and humeral hypersensitivity, r The freeing of more than one "forbidden" clone would result in an additional disorder(s) and would explain the frequent concurrence of these disorders. The similar immunoregulatory defect postulated for SLE could explain its apparent association with other autoimmune phenomena. Likewise, if sarcoidosis share.s a similar immunoregulatory defect, it might be anticipated that autoimmune disorders would occur in association with sarcoidosis in greater frequency than would be predicted by chance alone.

Uveitis and Sjogren Syndrome Both infectious and immunologic mechanisms have been raised as the etiologic basis of human uveitis. '~s Since double-stranded DNA and double-stranded RNA arc found in both SLE and uveitis, this has been used as evidence to suggest that they have similar immunologic and/or infectious mechanism(s) which may characterize the two disorders. 4s However, uveitis is uncommon in SLE with a cumulative percentage incidence of 0.8%.~ On the other hand, uvcitis is present in 20%--25% of patients with sarcoidosis. I'4 Sjogren syndrome is a chronic, inflammatory, autoimmun¢ disorder characterized by dryness of the eyes, mouth, and other mucous membranes. "s Up to 50% of these patients have an associated connective tissue disease. Using a battery of t e s t s , Alarcon-Segovia et al. concluded that there was evidence for clinical or subclinical Sjogren syndrome in practically all (greater than 90%) patients with SLE J and PSS.4 A more recent review demonstrated a lower incidence of Sjogren syndrome in PSS) ° In

136

sarcoidosis, only 4 cases of Sjogren syndrome were found in one series of 200 patients by James." However, using more sensitive tests, the Schirmer test and eye instillation of bengal pink, Crick et al. 33 found evidence for dry keratoconjunctivitis in 70% of his eases of sarcoidosis against 6% of his controls with varied eye disorders. An examination by a battery of tests such as those used on the patients with SLE and PSS would be of interest in patients with sarcoidosis and would probably yield a much higher incidence than previously reported.

Endocrinologic and Hematologic Autoimmune Disorders In animal models of spontaneous thyroiditis, the underlying factor appears to be a deficiency of suppressor T-cells. t2 The incidence of Hashimoto thyroiditis i s probably significantly increased in SLE'and averages about I% in several series of S LE patients." The association of thyroiditis and sarcoidosis has not received much attention until recently, but in a series of i45 patients, Mayock et al. t°° mentioned in passing that 2 patients (1.4%) had clinical findings of thyroiditis while in another series of 300 cases Karlish and MacGregor s~ described 4 patients (1.3%) with clinical evidence of Hashimoto thyroiditis. There is less evidence to suggest'a relationship of Graves disease with other disorders of immunoregulation. Approximately six cases of thyrotoxicosis have been reported coexisting with 5LE.26'4~"99"u° The simultaneous occurrence of Graves disease and PSS has been reported, m~° Hancock 6z recently reported five cases with thyrotoxicosis and sarcoidosis that were detected in a hyperthyroid clinic composed of 2100 patients. One case had sarcoidosis, thyrotoxicosis, vitiligo, and pernicious anemia, while another case had thyroiditis and sarcoidosis. He also reviewed the literature and described the 20 previously reported eases. He stated that it was impossible, with such a small series, to form conclusions on the relationship between sarcoidosis and thyrotoxicosis, but did mention that an association could result from an autoimmune disturbance resulting from loss of T-cell control. Thrombocytopenia is present in 14%--26% of

WtESENHU"/'FER AND SHARMA

patients with SLE s~84 and is usually due to a shortened platelet life span." Thrombocytopenia is far less common and less well studied in sarcoidosis, but Dickerma¢i et al. 4~ presented two cases and reviewed 37 more of sarcoidosis complicated by thrombocytopenia. The bone marrows that were available demonstrated normal to increased megakaryocytes in the majority, suggesting that the reduction in the number of platelets was on the basis of a shortened life span. The authors concluded that thrombocytopenia occurred with sufficient frequency to indicate that sarcoidosis may predispose to its development and that immunologic factors could be involved. Thrombocytopenia has been reported with PSS3 J Approximately 2%-6% of patients with SLE develop clinically d e t e c t a b l e hemolytic anemia, 63"~22"m and it is secondary to antierythrocyte antibodies, usually of the warm variety, and predominantly lgG. j7 Seven cases of autoimmune hemolytic ,anemia have been reported occurring with PSS. 23"98 In three eases where they were looked for, antierythrocyte antibodies were demonstrated. Dacie 3~reviewed 11 cases of hemolytic anemia and sarcoidosis and he believed the association was real. He noted that hemolytic anemia may coexist with, precede, or postdate by years sarcoidosis and that a clinical response was better with steroids than with splenectomy, suggesting that the hemolytic anemia was not on the basis of hypersplenism. A case report of sarcoidosis, thrombocytopenia, and hemolytic anemia has been describedJ 3~ Also, sarcoidosis has been reported to coexist with cold hemagglutinin disease, 1~8and this case was of further interest in that the patient had two sisters with rheumatoid a r t h r i t i s . The authors felt that this might be an example of a genetic disorder with an immunologic imbalance leading to a decreased cellular immunity and increased antibody response with autoantibody formation. There are several other autoimmune and related disorders that have been associated With connective tissue disorders and, on occasion, have been reported to coexist with sarcoidosis. However, these case reports are sporadic and the incidence of occurrence has not been analyzed systematically.

SARCOIDOSIS

THE ETIOLOGY AND PATHOGENESIS OF DERANGED IMMUNOREGULATION Loss of tolerance to self-antigens manifested by autoantibodics can occur without overt clinical disease, which is illustrated by the development of autoantibodies in elderly individuals who are apparently healthy. In addition, autoantibodies may be produced to self-antigens secondary to an alteration in host~tissue by nonimmune processes. These qualifications should be kept in mind when attempting to define the role of disordered immunoregulation in a specific disease state. Nevertheless, the recent studies performed on patients with common variable hypogammaglobulinemia demonstrated that, even when the dysfunction .of the suppressor cell system was secondary to another pathogenic mechanism (in this exam pie, defective B-cell function), the suppressor cell defect perpetuated and aggravated the disease (hypogammaglobulinemia)?67 Thus, even a secondary suppressor cell defect can be clinically significant and may require correction before other therapy is effective. New Zealand Mice

Three types of pathogenic mechanisms have been proposed to explain the development of the immunoregulatory defects in New Zealand mice: genetic, viral, and immunologic. Genetic Factors The exclusive association of the immunologic and pathologic processes in the two New Zealand mice strains convincingly establishes the genetic basis of the disease. However, it has been extremely difficult to elucidate the mode of inheritance of these disorders, though several genes apparently are involved. The potential for interaction between genetic factors and the immune system is immense. Some understanding of the complexed inter-relationship comes from studies of immune-response genes in animal models, m Viral Factors There is considerable evidence in support of viral factors playing a role in the causation of the immunoregulatory defect; C-type viral particles

137

are ubiquitous in the tissues of these animals. '°6 Viral antigens and antibody, comprising immune complexes, have been demonstrated in the kidney deposits of mice with glomerulonephritis. ~73 In addition, some of the manifestations of the disease have been transmitted to healthy recipients with cell-free filtrates of NZB tissues. ~°7 There are several models by which viruses could lead to defective immunoregulation.~49"~59 Some examples include: (A) host determinants could become incorporated in the capsid of a virus and ,the virus would then act as a carrier, allowing the self-antigen to become immunogenic; (B) infection by a virus could elicit a powerful nonspecific stimulatory signal from helper cells. Such a stimulus can be produced by injecting allogeneic cells into mice (the allogeneic effect),47 which can result in the production of autoantibodies and bypass the need for the antigen-specific T-cell help; (C) viral antigens, present on the lymphocyte membrane of suppressor and helper cells could distort intercellular communication resulting in the disruption of the intricate mechanism of regulation. This last hypothesis is especially attractive in that it allows for the apparent interplay between genetic and viral factors.149 The lymphocyte membrane can be viewed as a common meeting ground where genetically derived antigens, such as the histocompatibility antigens and the immune-response associated antigens (Ia), can interact with viral antigens. In concert, the presence of these antigens may deleteriously influence the immunoregulatory system. Immunologic Factors As previously discussed, the manifestations of New Zealand mice disease is most likely due to a defect in suppressor T-cells. There are two immunopathogenic mechanisms that could be responsible for the decline in suppressor T-ceU function. By 3 me of age, these raice develop a thymocytotoxic IgM antibody that is directed against T-cells and promotes their phagocytosis in vitro, m The significance of the antibody in rive has not been determined. Also, these mice have a progressive loss of thymosin-like activity (thymic hormones) that disappears completely by 2 me of age.s There is some evidence suggest-

W1ESENHUTTER AND SHARMA

138

ing that these substances are necessary for maintaining normal T-cell function, and, in the hands of some investigators, replacement has resulted in restoration ofT-cell function in vitro.

Systemic Lupus Erythematosus (SLE) The New Zealand mice are an excellent model for SLE, which is reflected by the fact that the pathogenic mechanisms postulated for SLE are similar to those suggested for the animal model.

Genetic Factors There is good evidence that SLE is more common in family members of patients with SLE, along with a higher familial incidence of other connective tissue diseases. 4° Genetic mechanisms have been proposed, 16't9 and both Xlinked alleles and autosomal loci may play a role.

Viral Factors The role for viral factors in SLE has been summarized elsewhere. 9~'1~° The evidence is indirect, but includes (A) the presence of tubuloreticular (virus-like) inclusions in several tissues; (B) elevated serum titers to a variety of viruses; (C) the detection of viral antigens, especially type-C related antigens, in a variety of tissues and on lymphocyte membranes. The possible mechanisms by which viral factors could lead to defective immunoregulation are analogous to those proposed for the New Zealand mice.

Immunologic Factors Waldman et al.,'67 in a recent review article, mentioned that preliminary research in his laboratory has now demonstrated a decrease in suppressor T-cells in SLE. As with the New Zealand mice, a defect in the suppressor regulatory system could explain the abnormalities in the immune system. The mechanism leading to a decrease in T-cell function has not been determined, but, as with the animal model, antilymphocyte antibodies have also been shown to be present in SLE tit and blood levels of thymic hormones are decreased. 6

Progressive Systemic Sclerosis (PSS) The etiology and pathogenesis of PSS remains obscure. Genetic and viral factors are not clearly

associated with this disease. What is known is that the earliest lesions appear to effect the vasculature, 2°'~S'~72while there are major alterations in the immune system, along with an abnormally increased collagen biosynthesis, s6 it has been suggested that a primary abnormality in the immune system could result in the production of lymphokines that have been known to stimulate connective tissue synthesis, 8° and thus cause the typical connective tissue changes of PSS. Support for the hypothesis that PSS is a result of defective immunoregulation stems from the recent reports 6~'9° describing the appearance of hypergammaglobulinemia, Sjogren syndrome, and PSS following bone marrow transplantation. These findings can be explained, if it is assumed that in this setting of a graft versus host reaction, an allogeneic effect occurs. '7 Thus, the allogeneic donor T-cells become activated, providing a powerful nonspecific helper T-cell signal to the host B-cells. Thes~ findings provide evidence that defective immunoregulation may be the primary pathogenic mechanism responsible for PSS and other autoimmune disorders.

Sarcoidosis Genetic Factors More than I ! 0 cases of familial sarcoidosis have been described, and sarcoidosis occurs more frequently in monozygotic rather than dizygotic twins, j~ James et al. 8° believed that a recessive mode of inheritance for sarcoidosis susceptibility may exist.

Viral Factors As with SLE, the evidence implicating viral factors in the pathogenesis of sarcoidosis is indirect but mounting and includes: (A) intracytoplasmie tubuloreticular structures that have been demonstrated in tissues; ~3 (B) increased serum antibodies directed towards a number of viruses;67"76(C) viral particles which have been shown to be present on the red blood cell membrane and in the kidneys of patients with glomerulonephritis; D°j'~26 (D) the presence in sarcoid tissue of a transmissible agent that is smaller than a bacteria and is possibly viable. ~t° This last experiment by Mitchell and Rees is the

139

SARCOIDOSIS

most convincing evidence that viral factors arc involved with the pathogenesis of sarcoidosis.

Immunologic Factors The relationship between sarcoidosis and connective tissue diseases and other autoimmune disorders was originally proposed, by Teilum in 1946. ~56 He noted the similarities between SLE and sarcoidosis and stated that the common features were hyperglobulinemia, a specific phasic development of"hyalinosis" in the reticuIocndothelial system which was sometimes found in direct relation to an accumulation of plasma cells, epitheloid cell granuloma without any tendency to necros¢, and periarterial hyaline zones in the spleen. He believed that the "'hyalinosis'" represented deposition of gamma globulin and thus postulated that sarcoidosis was a result of an "immunity reaction." In 1963, he ~57 emphasized t h e widespread distribution and location of the lesions in interstitial connective tissue o f patients with sarcoidosis, along with occasional involvement of the kidney and the relationship to purpura and hemolytic anemia as further evidence for its similarity to the group of "collagenosis." However, the inclusion of sarcoidosis into the group of disorders of autoimmunity has not been generally accepted. Sarcoidosis does not meet the criteria of Milgrom and Witebsky ~°9 for autoimmune diseases, though much of this difficulty may stem from the failure to isolate the inciting agent of sarcoidosis. The abnormalities and features of the immune system is sarcoidosis are consistent with the assumption that there is a defect in the suppressor regulatory system. To date, the evidence has been indirect, but methods for verification are becoming available. The evidence in this paper supports the contention that the mechanisms postulated for the pathogenc~is of the immuneregulatory defect in SLE can be equally well applied to sarcoidosis, and that, as with SLE, immunopathogenic processes contribute to the tissue injury in this disease, though to a lesser extent than in SLE. An interplay of both genetic and viral factors appear to be involved and may be responsible for a "'sarcoidosis diathesis." However, it is obviously an oversimplification to consider sarcoidosis as a disease of defective suppressor T-cells. Investigation of the immu-

noregulatory system is still in a stage of infancy, and the only major conclusion that can be currently drawn is that the mechanisms at work are extraordinarily complexed. Some of the unanswered questions include the clinical significance of primary versus secondary immunoregulatory defects. Also, the role of the "'activated" macrophage in sarcoidosis and SLE remains unknown, but the importance of this multifaceted cell in the immune system is becoming increasingly evident. Finally, the consideration of sarcoidosis as a disease of immunoregulation may have its greatest clinical significance in that methods developed for augmenting suppressor regulatory function may w e l l be applicable to sarcoidosis and could be prerequisite for ultimate therapeutic intervention. SUMMARY Four cases of sarcoidosis coexisting with connective tissue diseases are described: three cases of sarcoidosis coexisting with PSS, and one case of sarcoidosis coexisting With SLE. Reports of sarcoidosis combined with uncommon connective tissue diseases have been rare in the literature. The topic immunoregulation is briefly reviewed. A complexed system of both positive and negative regulatory factors arc responsible for generating and maintaining an optimum immune response. The cell types that participate in modulating this system are T lymphocytes, B lymphocytes, and macrophages. Recent work has shown that these major groups of cells can be further divided into functional subclasses such as the helper T-cell and the suppressor T-cell. Interaction between these cell type.s and the other cellular constituents of the immune response is carried out by means of humeral factors and direct cell-to-cell contact. Deranged immunoregulation has been shown to play a major role in the pathogenesis of several disease states, including the autoimmune disease of New Zealand mice, human SLE, agammaglobulinemia, and the immune-deficiencies of multiple myeloma, Hodgkin disease, and disseminated fungal infections. The role of defective immunoregulation in the animal model, New Zealand mice, is reviewed. The pathogenesis of this disease is most likely

W'IESENHUTTER AND SHARMA

140

due ,to defective suppressor T-cell function. A u g m e n t i n g suppressor function, by administering a humoral suppressor factor, has resulted in the d i s a p p e a r a n c e o f the manifestations o f the disease. Evidence in support o f the contention that sarcoidosis shares a similar defect of suppressor cell function with N e w Z e a l a n d mice, S L E , a n d possibly P S S is presented and includes: (1) A m a r k e d similarity in the features and a b n o r m a l i ties o f the i m m u n e s y s t e m between these diseases such as ( A ) A hyperactivity o f the humoral i m m u n e system; (B) A defect in several p a r a m e t e r s of cell-mediated i m m u n e function; (C) A loss of tolerance to self-antigens with the a p p e a r a n c e o f auto-antibodies and the development o f the m a n i f e s t a t i o n s o f c e l l - m e d i a t e d hypersensitivity. A n t i l y m p h o c y t e a n t i b o d i e s , most likely directed towards T-cells, can also be d e m o n s t r a t e d in S L E and sarcoidosis; (D) A depression o f a n t i b o d y dependent cell-mediated cytotoxicity in S L E and sarcoidosis. A n increase in null cells in both diseases can also be shown; and (E) S i m i l a r alterations o f circulating mono-

cytcs most likely representing activation o f these cells. Possibilities for the etiology and pathogenesis of the d e r a n g e d immunoregulation proposed for these diseases a r e discussed. A complicated interplay of both genetic and viral factors a r e likely to be involved in the causation of N e w Z e a l a n d mice disease, S L E , and sarcoidosis t h a t a r e u l t i m a t e l y expressed through alteration o f the intricate i m m u n o r e g u l a t o r y system. T h e immunologic features and abnormalities of these disease states a r e a manifestation of this defect. T h e potential t h e r a p e u t i c implications of these findings a r e discussed. The ability to m a n i p u l a t e various aspects of the i m m u n o r e g u latory system, such as a u g m e n t i n g suppressor function, m a y be applicable to both S L E a n d sarcoidosis a n d could be prerequisite for. ultimate t h e r a p e u t i c intervention.

ACKNOWLEDGMENT

We thank Paula Athanasion and Barbara Sachs for their secretarial assistance.

REFERENCES

I. Abe T, Homma M: Immunological reactivity in patients with systemic erythemato~us. Acta Rheumatol Scand 17:35---46,1971 2. Asherson GL, Zembala M: Suppressor T cells in cellmediated immunity. Br Mud Bull 32:158-164, 1976 3. Alarcon-Segovia D, lbancz G. Velazquez-Forer0 F, et al: Sjogren's syndrome in systemic lupus ¢rythematc6us. Ann Intern Mud 81:577-583, 1974 4. Alarcon-Segovia D, Ibanez G. Velazquez-Forero F, et al: Sjogren's syndrome in progressive systemic sclerosis (Scleroderma). Am J Mud 57:78-85, 1974 5. Bach JF, Dardcnne M. Salomon JC: Studies on thymus products. IV. Absence of serum "thymic activity" in adult NZB and (NZB X NZW) FI mice. Clin Exp lmmunol ! 4:247-256, 1973 6. Bach JF, Darderm,: M. Clot J: Evaluation of serum thymic hormone and of circulating T cells in rheumatoid arthritis and in systemic lupus. International Symposium on Immunity of Rheumatic Diseases. Montpelier. April 1974 7. Baker PJ: Homeostatic control of antibody responses: A model based on the recognition o1"cell-associated antibody by regulatory T cells. Transplant Rev 26:3-20. 1975 8. Ballard JL, Snyder CR, Jansen GT: The gastrointestinal manifestations of generalized sclcroderms. South Mud J 62:1243-1247. 1969 9. Bara J, Marche J. Nctter FC, et al: Syndrome de Gougerot-Sjogren revelatcur d'une sclerodcrmie et d'unc maladie de Besnier-Boeck-Schaumair. Rev Stomatol Chir Maxiilctac 74=357-377, 1974 10. Barfeld AS, Streda A: Sarcoidosis and rheumatoid

arthritis, in: Levinsky L, Macholda F, eds. The 5th International Conference on Sarcoidosis. Praha. Universita Karlova, 1971, 597-598 ! I. Barnett EV, Kantor G. Bickel YB,'et ah Systemic lupus crythematosus. Calif Med I 11:467--481, 1969 12. Beall GN: Clinical immunology of Hashimoto's disease, in Brown J (moderator): Autoimmune thyroid diseases---Graves" and Hashimoto's. Ann Intern Mud 88:379-391. 1978 13. Bernaudin JF. Soler P, Basset F: Intracytoplasmic tubuloreticular structures in 2 cases of sarcoido~is and 2 cases of malignant pleural mesothelioma. Pathol Eur 8:277, 1973 14. Bitter T: SLE: Antinuclear serology a~d cellmediated immunity in the light of clinico-hematologic diagn~tic criteria. Schweiz Mud Wochenschr 101:181-186, 1971 15. Brincker H. Wilbek E: The incidence of malignant tumors in patients with respiratory sarco/dosis. Br J Cancer 29:247-251, 1974 16. Buckman KJ, Moore SK, Ebbin A J: Familial systemic lupus erythcmatosus. Arch Intern Mud 138:1674--1678, 1978 17. Budman DR, Steinberg AD: Hematologic aspects of systemic lupus erythcmatosus. Ann Intern Mud 86:220-229, 1977 18. Budman DR. Merchant EB, Steinberg AD. et al: Increasod spontaneous activity of antibody-forming cells in the peripheral blood of patients with active SLE- Anhriti.~ Rheum 20.829--833. 1977

SARCOIDOSIS

/19. Burch PRJ, Rowell NR: Systemic lupus crythematosus. Etiological aspects. Am J Mud 38:793---801, 1965 20. Campbell PM, LeRoy ~EC: Patbogenesis of systemic sclerosis: A vascular hypothesis. Semin Arthritis Rheum 4:351-368, 1975 21. Canoso J J, Cohen AS: Malignancy in a series of 70 patients with systemic lupus erythcmatosus. Arthritis Rheum 17:383-390. 1974 22. Cantor H, As&sky R: Syne~gy among lymphoid cells mediating the graft versus host response. Ill. Evidence for interaction between two types of thymus-derived cells. J Exp MOd 135:764-779, 1972 23. Carcassonne Y, Gastant JA: Pancytopenia and seleo roderma. Br Mud J 1(60--23):1446, 1976 24. Carrington CB, Gaenslcr EA. M~;kusJP, et al: Structure and function in sarcoidosis. Ann NY Acad Sci 278:265282, 1976 25. Chapman JS, Clark J: Cold-precipitable proteins in sarcoidosis sera, in Levisky L" l~lacholda ~F (eds): The 5th International Conference on Sarcoidosis. Praha, Universita Karlova 197 I, pp ! 98-202 26. Chcah .IS, Chia BL, Tay HH. et ah Hyperthyroidism in systemic lupus erythematosus. Mud :J Aust 2:1029-1030, 1970 27. Chorz.elski TP. Beutner EH, Jablonska. S. et al: Immunofluorescence studies in the diagnosis of dermatitis herpetiformis and its differentiation from bullous pomphigold. J Invest Dcrmatol 56:373-380, 1971 28. Chused TM. Kassan SS. Mosier DE: Macrophage requirement for the in vitro response to TNP ficoll: A thymic independent antigen. J Immunol ! 16:1579-158 i, 1976 29. Claman HN. Chaperon EA: Immunologic complementation between thymus and marrow cells: A model for the two cell theory of immunocompetence. Transplant Rev 1:92-113. 1969 30. Cipolctti JF, Buckingham RB. Barnes EL. ¢t ah Sjogrcn's syndrome in progressive systemic sclerosis. Ann Intern Mud 87:535-541. 1977 31. Clark JA, Winkelmann RK. McDuffie FC, et ah Synoviai tissue changes and rheumatoid factor in scleroderma. Mayo Clin Prce 46:97-I 03, 1971 32. Clinc MJ,'Lehrer RI, Territo MC. ©t ah Monocytes and macrophages; Functions and diseases. Ann Intern MOd 88:78-88, 1978 33. Crick RP. Hoyle C, Smellie H: The eyes in sarcoid¢~is. B r J Opth 45:461-468o 1961 34. Daeie JV: The haemolytie anaemias. Vol. Ill. 2rid ed., London: Churchill Livingstone, ! 967, p. 921 35. Danicle RP, Rowlands DT: Lymphocyte subpopulations in sarcoidosis: Correlation with disease activity and duration. Ann Intern Mud 85:593:-600, ! 976 3 6 . Dani¢le RPo Rowlands DT, Jr. Antibodies to T cells in sarcoidosis~ Ann NY Aead Sci 278:88-100, 1976 37. Dauphinne M J, Talal N, Goldstein AL: Thymosin corrects the abnormal DNA synthetic t;esponse of.NIZB mouse thymocyte. Proc Natl Aead Sci U S A 71:2637-2641, 1974 3 8 . Dcicher HR, Holman HR.KunkelHG:Anticytoplasmic factors in t h e sera of patients with systemic lupus erythematosus and certain other diseases.-Arthritis Rheum 3:!-!5, 1960

141

39. de Jesus DG, Clancy RL: Circulating T a n d B lymphocytcs in progressive systemic sclerosis. J Rheumatol 2:336-339, 1975 40. Dclbarre Fo G o AL, Kahan A: Hyperbasophilic immunoblasts in the circulating blood in chronic inflammatory rheumatic and collagen diseases. Ann Rheum• Dis 34:422--430, 1975 •41. Dickerman JD, Holbrook PR, Zinkham WH: Etiology and therapy of thrombocytopenia associated with sarcoidosis. J Pediatr 81:758-764, 1972 42. Douglas SD, Daughaday CC, Schmidt ME. et ah Kinetics of monocyte receptor activity for immunoproteins in patients with sarcoidosis. Ann NY Acad Sci 278:190-200, 1976 • 43. Dubois EL: Lupus Erythematosus (ed 2). Los Angeles, University of Southern California.Press, 1974 44. Dubois EL, Chandor S, Friou G J, et ah Progressive systemic sclerosis and localized sclerod~'ma with positive LE cell test and unusual systemic manif~tations compatible with systemic lupus erythematosns. Medicine (Baltimore) 50:199-222, 1971 45. Dubois EL, Commons RR, Start P, ct ah Corticotropin and cortisone treatment [or systemic lupus crythematosns, JAM A 149:995-1002. t 952 46. Dubois EL, Tuffanelli DL: Clinical manifestations of systemic lupus erythematosus. JA MA190:104-1 ! 1° 1964 47. Elkins WL: Cellular immunology and the pathogcnesis of graft versus host reactions. Prog Allergy 15:78-187, 1971 48, Epstein WV, Tan M, EastcrbrookM: Serum antibody to double-strapded RNA and. DNA in patients with idiopathic and secondary uvcitis. N Engl J Mud 285:1502-1506, 1971 49. Feldmann M; Basten A: Specific collaboration between T and B lymphocytes across a cell impermeable membrane in vitro. Nature (New Biol) 237:i3, ! 972 / 50. Forrnan J, Moiler G: The effector cell in antibodyinbluced celi-medlated immunity. Transplant R e v 17:!98, i 973 51. Fries JF: The clinical aspects of systemic lupus erythcmatosus- Mud Clin North Am 61:229-240, 1977. 52. Fries JF, Holman HR: Systemic LLspus Erythematosusl Philadelphia, Saunders, 1975. ' 53. Garg SK, Amorosi EL, Karpatkin S: Use of the megathrombocyte a s a n index of megakaryceyte number, N Engl J Mud 284:11-17,r197i 54. Gerber MA: Immunohistochemical findings in the renalvascular !~ions of progressive systemic sclerosis. Hum Pathol 6:343=347, 1975 55. Gershon RK, Liebhaber S, Ryu S: T-cell regulation of T-cell responses to antigen: lmmunol 26;909,923, i 974 56- Gershwin ME, Steinberg AD: Suppression ofautoimmune hemolytic anemia in New Zealand (NZB)mice by syngeneic young thymocytes. Clin Immunol Immunopatbol 4:38-=45, ! 975 . 57. Gery I, Waksman BH: Potentiation of the T-lymphocyte response to mitogcns. II. The cellular source of potentiating mediators. J F.xp MOd 136:i43, 1972 . .: 58. Gery l , Handschumacher RE: Potentiation of the T lymphocyte response t o mitogens,. 111. Properties o f S-he

142 mediator(s) from adherent cells. Cell lmmunol 1!:i62-169, 1974 59. GhoseT. Landrigan P, Asif A: Localization of immunoglobulin and complement in pulmonary sarcoid granulomas. Chest 66:264-268. 1974 60. Glinski W. Gershwin ME. Badman DR, ¢t al: Fractionation of cells on a discontinuous ficoli gradient. Study of peripheral blood lymphocyte subpopulatious in ~ormal humans and patients with systemic lupus erythematosus. Clin Exp Immunol 26:228-238. 1976 61. Gratwhol A, Moutsopoulos HM, Chused TM, et al: Sjogren type syndrome after allogenic bone marrow transplantation. Ann Intern Mud 87:703-706. 1977 62. Hancock BW, Millard LG: Sarcoidosis and thyrotoxicosts. A study of five patients. Br J Dis Chest 70:129-133, 1976 63. Harvey AM, Shulman LE, Tumulty PA, el ah Systemic lupus erythematosus: Review of the literature and clinical analysis of 138 eases. Medicine 33:291-437, 1954 64. Haustein UF, Beckmann I, Itaustein B, et al: Immunologic reactivity to incompatible blood substances of the ABO system in scleradcrma. Acta Biol Mud Germ 34:14171420, 1975 65. Hedfors E, Norberg R : Evidence for circulating immune complexes in sarcoidosis. Clin Exp lmmunol i 6:493--496, 1974 66. Hedfors E, Holm G, Pettersson D: Lymphocyte subpopulations in sarcoidosis. Clin Exp lmmunol 17:219226, 1974 67. Hirshaut Y, Philip G, Octavio L: Sarcoidosis. another disease associated with serologic evidence for herpes-like virus infection. N Eng] J Mud 283:502-506, 1970 68. Hof[brand BI: Occurrence and significance of lymphopenia in sarcoidosis. Am Rev Respir Dis 98:i07-110. 1968 70. Horwitz DA, Garctt MA: Lymphocyte reactivity to mitogens in subjects with systemic lupus erythcmatosus. rheumatoid arthritis, and sclerodcrma. Clin Exp Immunol 27:92-99, 1977 . 71. Howic JB. Helyer BJ: The immunology and pathology of NZB mice. Adv immunol 9:215-266, 1968 72. Huges P, Holt S. Rowell NR, e t a h The relationship of defective cell-mediated immunily to visceral disease in systemic sclerosis. Clin Exp I mmunol 28:233-240, 1977 73. Hurd ER. Dowdlc Wo Casscy H. Ziff M: Virus antibody levels in systemic lupus erythematosus. Arthritis Rheum 15:267-274. 1972 74. Husson JM. Druet P, Contet A. et ah Systemic sclerosis and cryoglobulinemia. Clin immunol Immunopath 6:77-82, 1976 75. Israel HL, Patterson JR.Smukler NM: Latex fixation tests in sarcoiditis, in Lofgren S. Kungl Boktryckeriet PA (eds): The 3 r d International Conference on Sarcoiditis. Stockholm, Norstedt & Soner. 1964, pp 40-42 76. James DE;, Neville E, Walker A: Immunology of sarcoidosis. Am J Mud 59:388-394. 1975 77. • James DG: Ck.*ular sarcoidosis. Am J Mud 26:331339. 1959 •78. James DG, Piyasena KHG. Nev'l;e E, e t a h Possible genetic influences in familial sarcoidosis. Postgrad Mud J • 50:664--670, 1974

WIESENHUTTER AND SHARMA 79. James DG, Neville E. Carstairs LS: Bone and joint sarcoidosis. Strain Arthr/tis Rheum 6:53. ! 976 80. Johnson RL. Ziff M: Lymphokine stimulation of collagen accumulation. J Clin Invest 58:240-252. i 976 81. Jones JV, Cumming RH. Asplin CM: Evidence for circulating immune complexes in erythema nodosum and early sarcoidosis. Ann NY Acad Sci 278:212-21L. 1976 82. Kalden JR, Peter HH. Lohmann E, et al: Estimation • ofT- and K-cell activity in the peripheral blood of sarcoidosis patients. Ann N Y Aead Sci 278:52--67, 1976 83. Kariish A J, MacGregor GA: Sarcoidosis, thyroiditis and Addison's disease.Lancet 2:330, 1970 84. Karpatkin S. Garg SK, Siskind GW: Autoimmune thrombocytopcnic purpura and the compensatedthrombocytolytic state. Am J Mcd 51:1-4, 1971 85. Kirchner H, Muchmore AV. Chused TM, etah Inhibition of proliferation of lymphoma ceils and T lymphocytes by suppressor cells from spleens of tumor-bearlng mice. J Immunol 114:206-210, 1975 86. Keiser ltR, Stein HD, Sjoerdsma A: Increased protocollagen proline hydroxylas¢ activity and sclerodermatous skin. Arch Dcrmatol 104:57-60. 1971 87. Klempercr P. Pollack AD, Baehr G: Pathology of disseminatcd lupus erythematosus. Arch Pathol (Chicago) 32:569-631. 1941 88. Kolb J. Arrian S. Zolla-Pazncr S: Suppression of the humoral immune rcspofise by plasmacytomus: Mediation by adherent mononuclear cells. J lmmunol I ! 8:702-709, 1977 89. Blease RM: T-suppressor ceils as mediators of"infectious agammaglobulincmia" of birds, in Waldmann TA (moderator): Disorders of suppressor immunoregulatory cells in the pathogenesis of immunodeficiency and autoimmnnity. Ann Intern Mud 88:226-238, 1978 90. Lawley T J, Peck GL, Moutsopoul.os HM. et ah Scleroderma Sjogrcn-like syndrome, and chronic graftversus-hostdisease.Ann Intern Mud 87:707-709, 1977 91. Lee SL, Rivcro I: Cryoglobulins in SLE as circulating immune complexes.Arthritis Rheum 7:321. 1964 (abstr) 92. Levy J: Autoimmunity and ncoplasia: The possible role of C-type viruses. Am J Clin Pathol 62:258-280, 1974 93. Lewis RB. Castor CW. Kinsley RE, e t a h Frequency of neoplasia in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 19:1256--1260, 1976 94. Liebow AA: The J Burns Amlxrson Lecture: Pulmonary angiitis and granulomatosis. Am Rev Respir Dis 108:119. 1973 95. Lies, RB. Mcssner RP, Williams RC Jr.: Relative T-cell specificity of lymphocytotoxins from patients with SLE. Arthritis Rheum 16:369-375, 1973 96. Light foot RW Jr: Systemic lupus erythematosus as an immune complex disorder, in Hughe~ GRV (ed): Modern Topics in Rheumatology. London, W. Heinemann Medical Books, 1976, pp 92-98 97. Lipsky PE, Rosenthal AS: Macrophage-lymphocyte interaction. !1. Antigen-mediated physical interactions between immune guinea pig lymph node lymphocytes and syngencic macrophages. J Exp Mud 14hl38-154, 1975 98. Loll B, Olscn F: Autoimmune haem01ytic anemia with positive Ham and Crosby's test and Scleroderma. A case report. Scand J Haematol 1 i:!31-134. 1973

SARCOIDOSIS

99. MacKay IR, Perry BT: Autoimmunity in human thyroid disease. Aust Ann Med 9:84-92, 1960 100. Mayock RL, Bertrand P, Morrison CE, et ale Manifestations of sarcoidosis. Analysis of 145 patients with a review of nine series selected from the literature. Am J Mud 35:67-89, 1963 101. McCoy RC, Tisher CC: Glnmen/Ionephritis associated with sarcoidosis. Am J Pathol 68:339-354, 1972 102. McDevitt H a , Bodmer WF: HL-A, immuneresponse genes and disease. Lancet 1:1269-1275, 1974 103. McGiven A, deBoer WGRM, Path MC. et ale Autoantibodies in scleroderma. M u d J Aust 2:533-536, 1968 104. Mellors RC: Immunological and virological aspects of leukemia lymphoma experimental marine model and its clinical relevance, in Zarafonetis JD (cd): Proceedings of the International Conference on I_~ukemia and Lymphoma. Philadelphia, Lea & Febiger, 1968. p '203 105. MeUors. RC: Autoimmune discaseand neoplasia of NZB mice. Experimental model and its implications, in Rose NR, Milgrom F {eds): International Convocation on Immunology, Buffalo, 1969. Basel. Karger, 1969, p 222 106. Mellors RC, Aoki 1", Hucbner R J: Further implication of routine leukemia-like virus in the disorders o1"NZB mice. J Exp Mud 129:!045-1062. 1969 !07. Mellors RC. Huang CY: lmmunopathology of NZB/BI mice+ V Viruslike (filtrable) agent separable from lymphoma cells and identifiable by electron microscopy. J Exp Mud 124:1031-1038. 1966 108. Messner RP. Lindstrum FD. Williams RC Jr: Peripheral blood lymphocyte cell surface markers during .the course of systemic lupus erythematnsus. J Clin laves 52:3046--3056, 1973 109. Milgrom F, Witebsky E: Autoantibodies and autoimmune diseases. JAMA 181:706-716, 1962 !I0. Mitchell DN. Rees ILI: The nature and physical characteristics of a transmissible agent from human sarcoid tissue. Ann NY Acad Sci 278:233-247, 1976 11 !. Mittal KK, Rossen RD, Sharp JT, et ale Lymphocyte O+totoxic antibodies in systemic lupus erythematosus. Nature 225:1255--! 256, 1970 112. Mosier DE: Cell interactions in the primary immune response in vitro: A requirement for specific cell clusters. J Exp Mud 129:351-362, 1969 113. Mulhern LM. Masi AT. Shulman LE= Hashimoto°s disease. Search for associated disorders in lT0 clinically detected cases. Lancet 2:508--512. 1966 114. Neville F., Mills RGS, James DG: Sarcoidosis of the upper respiratory tract and its relation to lupus pernia. Ann NY Acad Sci 278:416--425, 1976 i i 5. Norton WL. Nardo JM: Vascular disease in progressivesystemiesclerosis. Ann Intern Mud 73:317-324, 1976 116. Oklek K: Disseminated lupus erythematosus occurring i n the course of sarcoidosis. Ppl Arch Mud Wewnet 40:641-644, 1968 - ' : • 117. Oreskes 1, Siltzbach LEe Changes in rheumatoid factor activity during th= course of sarcoidosis, Am J Mud 44:60--67, 1968 • 118~ Palazzo E. Oberling F, North ML, et ale Sarcoidosis and cold haemagglutinin disease. Acta Haematol 4g'.331336,1972 " ~ ~"~"" " +- "-' .... " " " + .+ "

14,3

i 19. Paola DE: Disseminated lupus erythematosus with sarcoid granuloma, Frankfurter Zeitschrift f'dr Pathnlngie 69:363-373, 1958 120. Papadopoulos C, Jiji R, Maher E: Lupus erythematosus and hyperthyroidism. Am J Dis Child 118:621-625. 1969 121. Phillips PE: The virus hypothesis in systemic lupus erythematosus. Ann Intern Mud g3:709-715, 1975 122. Pisciotta AV, Gilibcrt JJ, Grcenwalt T J, et ale Acute hemolytic anemia in disseminated lupus erythematosus Treatment with cortisone. Report of a case. Am J Clin Path 21:1139-1144, 1951 123. Pollack AD: Some observations on the pathology of systemic lupus erythematosus. J Mount Sinai Hasp NY 26:224-240, ! 959 124. Putkonen T, Virkkunen M. Wagner O: Joint involvement in sarcoidosis with special reference to the coexistence of sarcoidosis and rheumatoid arthritis. Acta Rheum Scand I 1:53--61, 1965 125. Quismor/a FP, Sharma a m P, Chandor S: lmmunopathological studies on the cutaneous lesions in sarcoidosis. Br J Dermatol 97:635-642. i 977 126. Reagan RL, Palmer Ed, Ddaha EC, et ale Study by electronmicroscopy of erythrocytes from a patient affected with sarooidosis. Texas Reports Bin Mud i 3:350-361, 1955 127. Refvem O, Bjomstad RT. Lx~ K: The ornithosis complement fixation test in sarcoidosis. Ann N Y Acad Sci 278:225-232. 1976 128. Rosen Y, Moon S. Huang C. et ale Granulomateus pulmonary angiitis in sarcoidosis. Arch Pathol Lab Meal 101:170-174, 1977 129. Rothfield NF. Evans AS. Niederman-JC: Clinical and Laboratory aspects nf raised virus antibody liters in systemic lupus erythematosus. Ann Rheum Dis 32:238-246, 1973 130. Salem NB, Morse JH: Lymphocyte response to mitogens in progressive systemic sclerosis. Arthritis Rheum 19:875-882, 1976 131. Salo OP, Hannuksela M: Immunohistology of the Kveim r~ction. Ann Clin Res 4:169. 1972 132. Sands JH, Palmer PP, Mayock RL. et ale Evidence for serologic hyperractivity in sarcoidosis. Am J Mud 19:401-409, 1955 133. Schneider J, Chin G. Friou G J, et ale Reduced antibody-dependent ceil-mediated cytotoxicity in lupus erythunatosus. Clin Exp Immunol 20:i87-192. 1975 134. Scornik JC. Cesenza H. Lee W, KhMer, ct ale Antibody dependent nell-mediated cytotoxicity. J Immunol 113:.1510-1518, 1974 135. Sample PDA: Thrnmbocytopenia, Haemolytic anemia, and sarcoidmis. Br Mud J 4 (5994):44~441, 1975 136. Sharma 'OP, Neville E: Familial sarcoidosis: A possible genetic influence. Ann NY Acad Sci 283:386-400, 1976 137. Sharma aPe Sarcoidcsis: A Clinical Approach. Springfield, Bamaerstone House, 1975 138. Shearn MA: Sjogren's Syndrome. Mud Clin North Am 6I:271-282, 1977 139. Shirai T, Mellors RC:' Naturnl thymocytotoxic auteantibody and reactive antigen in New Zealand black and other mice. Proc Natl Acad Sci USA 65:1412, 1971

144

WIESENHUTI'ER AND SHARMA

140. Shoaleh-var M, Houshmand Montaz A., Jamshidi C: Scleroderma and hyperthyroidism. JAMA 235:752-753, i 976 141. Shulman LE, Kurban AK, Harvey AM: Tendon friction rubs in progressive systemic sclerosis (scleroderma). TransAsscc Am Physicians 74:378-388, 196J 142. Siltzbach LE, James DG° Neville E, et al: The course and prognosis of sarcoidosis around the world. Am J Mcd 57:847-852, 1974 143. Siltzbach LE: Significance and SlXCificity of the Kveim reaction. Acta Mad Scand (Suppl) 425:74--78, 1964 144. Silverstein AM: Immunopathology of aveitis. Balti. more, Williams & Wilkins, 1964 145. Spilbcrg I, Siltzbaeh LE, McEwen C: The arthrhis of sarcoidosis. Arthritis Rheum 12:126-137, 1969 146. Stastny P, Ziff M: Cold insoluble complexes and complcment levels in SLE. N Engl J Mad 280.'1376--1381, i 969 ! 47. Steinberg A, Gershwin M E, Gerber N. et ahRole of suppressor cells in the pathog©nesis of autoimmunity in New Zealand mice. in: Sisking GW. Christian C (¢ds): Immune Depression and Cancer. New York, Grune &. Stratton, ! 975,

p42 148. Stobo JD. Paul S. 3fan Scoy RE, e: ah Suppressor thymus-derived lymphocytes in fungal infection. J Clin Invest 57:319-328. 1976 149. Talal N: Immunologic and viral factors in autoimmane diseases. Meal Clin North Am 61:205-215, 1977 150. Talal N: Animal models for systemic lupus erythematosus. Clin Rheum Dis ! :485-498. 1975 151. Talal N:Autoimmunityand lymphoid malignancy in New Zealand black mice. in: Schwartz RS (ed): Progress in Clinical Immunology. New York: Grune & Stratton, 1973, pp 101-120 152. Talal N: Pathogcnesis of systemic lupus erythcraatosus. West J Mcd 122:157-158, ! 975 153. Taibott JH, Barrocas M: Progressive systemic sclerosis (PSS) and malignancy, pulmonary and nonpulmonary. Medicine (Baltimore) 58:182-207. 1979 154. Taniguchi M, Tada 1"." Regulation of homocytotrophic antibody formation in the rat. lgT-iikc molecule for the induction of homocytotropic antibody response. J Immunol I 13:1757-1769, 1974 155. Taussig M J+ Munro A J: Removal ofspceific cooperative T cell factor by anti-H-2 but not by anti-lg sofa. Nature 251:63-64, 1974 156. Teilum G: Pathogenetic studies on lupus e~thcmatosus disseminates and rchted diseases. Acla Mad Stand 123:126--142, 1946 157. Teilum G: Morphogenesis and development of sarcoid lesions, Sinailarities to the group of collagenusis, ia: Lofgreus, Kungl IBoktryckerict PA (ads): The 3rd International Conference on Sarcoidosis: Stockholm, Norstedt & Sonar, 1964, pp 14-18 - : 158. Tcilum G: Miliary cpithelioid,cell granulomas in lupus ew~cmato~us disscminatus. Acta Pathol Microbiol Scand 22:73-79. ! 945 ~

'

- -

"

" l

159. Thaler JS, Lausncr RD," Cohe n H J: Medical Immunology. Philadelphia, JB Lipphl.cott Co.. 1977, pp 85 160. Tigelaar RE, Asofsk:y R: Synergy among lymphoid cells mediating a graft-ve,,'sus-host response. V. Derivation by migration in lethally iCradiatcd recipients of 2 interacting subpopulations of thym4zs-derivcd cell from normal spleen. J Exp Mad 137:239-25~1, 1973 161. Twomey JJ, Laughter AH. Farrow S, el ai: Hodgkin*s disease: An tmmunodepleting and immunosuppressive disorder. J Clin Invest 56:467-475, 1976 162. Uhr JW. Moiler G: Regulatory effect of an antibody on the immune response. Adv Immunol 8:81-127, 1968 ! 63. Unanue ER: The regulatory role of macrophages in antigenic,stimulation. Adv Immuno115:95, 1972 164. 'Veien NK, Hardt F, Bendixcn G, et ah Immunological studies in sarcoidosis: A comparison of disease activity and'various immunological parameters. Ann NY Acad Sci 278:47-5 !, 1976 165. Vol~: R: The role of autoimmunity in hypoendocrine and hypercndocrine function. Ann Intern Mad g7:86-99, 1977 166. Waldmann TA, Brodcr S: Suppressor cells in the regulation of the immune response, in: Schwartz RS (ed): Progress in Clinical Immunology. New York. Grune & Stratton, 1977, 155-199 167. Waldmann TA (moderator)° Blaese RM, Broder S, etal: Disorders of suppressor immunoregulatory cells in the pathogcnesis of immunodcficicncy and autoimmunity. Ann lntera Mcd 88:226-238, 1978 168. Waldman SR, Gottlieb AA: Macrophage regulation of DNA synthesis in lymphoid cells: Effects of a soluble factor from macrophagcs. Cell l mmunol 9:142, 1973 169. Waldron JA Jr.. Horn RG, Rosenthal AS: Antigeninduced proliferation of guinea pig lymphocytc~ in vitro: Obligatory role of macrophagcs in the recognition of antigen by immune T-lymphocytes. J Immunol I ! 1:58-64, 1973 170. Wanstrup J, Elling P: immunohistochemistry of sarceidosis. Acta Pathol Microbioi Scand 73:37-48. 1968 171~ Weans JH. Schwartz RS: Etiologic factors in heron. lyric anemia. Set Hacmatol 7:303:327, 1974 172. Winkclmann RK: Pathogcnesis a n d staging of scD:.rodcrma. Acta Dermai61 (Stockholm) 56:83-92. 1976 1")3. Yoshiki T. Mellors RC, Strand M. ¢t a h The viral envelope glyco-protcin of muriric leukemia virus and the pathogenesisof immune complexglomerulonephritls of New Zealand mice. J Exp Mad 140:1011-1027, 1974 174. Yoshinaga M. Yoshinaga A, Waksman BH: Regulation of lymphocyte responses in vitro. 1. Regulatory effect Of macrophages and thymus-dependent.(T') cells o n t h e response of thymus-independent (B) iymphocyte~ to endotoxin. J Exp Mad 136:956-961. 1972 . 175. Zingale SB, Sanchez Avalos JC. Andrada JA. et ah Appearanceof anticoagulant factors and certain "autoimmune" antibodies following antigenic stimulation with blood group substances in patients with systemic lupus erythematosus. Arthritis Rheum 6:581-598. 1963 . . . . .....