ARTICLES

A Diffuse Infiltrative CD8 Lymphocytosis Syndrome in Human Immunodeficiency Virus (HIV) Infection: A Host Immune Response Associated with HLA-DR5 Silviu Itescu, M D ; Lenore J. Brancato, M D ; Joel Buxbaum, M D ; Peter K. Gregersen, M D ; Ciril C. Rizk, M D ; T. Scott Croxson, M D ; Gary E. Solomon, M D ; and Robert Winchester, M D

Study Objective: To describe the clinical, immunologic, and immunogenetic features of a diffuse infiltrative lymphocytic disorder resembling Sjogren syndrome in persons infected with human immunodeficiency virus (HIV). Design: Clinical case study. Setting: University-affiliated hospitals and outpatient clinics. Patients: Consecutive sample of 17 patients. Measurements and Main Results: All of the 17 patients had bilateral" parotid gland enlargement; 14 had xerostomia and 6 had xerophthalmia. Of the 17 patients, 14 had generalized lymphadenopathy, 10 had histologically proved lymphocytic interstitial pneumonitis, 4 had neurologic involvement, and 3 had lymphocytic infiltration of the gastrointestinal tract. Gallium scanning in all of 11 tested patients showed abnormal salivary gland uptake. Minor salivary gland biopsies showed more than 2 lymphocytic foci per 4 mm2 tissue in all of 11 tested patients, the infiltrate consisting predominantly of CD8 cells. Fifteen patients had circulating CD 8 lymphocytosis; the principal phenotype of these cells was CD8 + CD29 + . Rheumatoid factor and antinuclear antibodies were infrequent, and none of the patients had anti-Ro/SS-A or anti-La/SS-B antibodies. HLA-DR5 was significantly more frequent in the black patients (10 of 12) compared with controls (13 of 45). Only one patient developed an opportunistic infection during 544 patient-months of study, and none has died of AIDS. Conclusions: A distinct syndrome primarily characterized by parotid gland enlargement, sicca symptoms, and pulmonary involvement occurs in HIV infection. This disorder is associated with CD 8 lymphocytosis and the presence of HLA-DR5, and appears to be a genetically determined host immune response to HIV.

Infection with the human immunodeficiency virus (HIV) may give rise to clinical manifestations other than those associated with frank immunodeficiency ( 1 ) . However, the particular circumstances governing the progression of HIV infection and its varied consequences in individual patients are unclear. Host factors, such as major histocompatibility complex ( M H C ) antigens, may influence H I V disease manifestations by regulating the immune response to the virus. A n increased frequency of HLA-DR5 has been reported in persons infected with HIV who develop either persistent generalized lymphadenopathy (2) or Kaposi sarcoma ( 3 ) , and HLA-DR1 (4) and HLAD R 3 (5) have been associated with an accelerated progression to frank acquired immunodeficiency syndrome ( A I D S ) . Although CD4 cell depletion is the most prominent feature of H I V infection, various other cell lineages are also affected. Many patients have a moderate increase in C D 8 lymphocyte numbers early in the course of HIV infection ( 6 ) . This lymphocytosis is generally transient with the number of C D 8 cells subsequently declining in parallel with progressive C D 4 cell depletion. In some patients, however, elevated levels of C D 8 cells persist and have been seen in occasional instances of disseminated visceral lymphocytic infiltrates (7) or lymphocytic interstitial pneumonitis ( 8 ) . We describe a clinical syndrome, previously presented in preliminary form ( 9 ) , that is characterized by persistent circulating C D 8 lymphocytosis and diffuse lymphocytic tissue infiltration in persons infected with HIV. Although this disorder clinically resembles Sjogren syndrome, it differs in some immunologic and immunogenetic features. In particular, H L A - D R 5 is greatly more prevalent in black patients with this disorder, suggesting that the diffuse infiltrative lymphocytosis syndrome may reflect a distinctive host immune response to HIV that is critically dependent on a particular M H C class II allele. Case Histories Patient 3

Annals of Internal Medicine. 1990; 112:3-10 From New York University Medical Center, New York Veterans Affairs Medical Center, and Beth Israel Medical Center, New York, New York. For current author addresses, see end of text.

A 3 8-year-old black male intravenous drug user presented with an 8-month history of bilateral facial swelling and severe dryness of the mouth and eyes. Over the previous month, he had also noted progressive exertional dyspnea as well as abdominal discom-

© 1990 American College of Physicians

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

3

fort and early satiety. Physical examination showed massive bilateral parotid gland enlargement and cervical adenopathy. H e also had a non-tender midepigastric mass. Tests for HIV were positive by both enzyme-linked immunosorbent assay ( E L I S A ) and Western blot analysis. The patient's leukocyte count was 9.2 X 10VL with 3 1 % lymphocytes. He had 427 C D 4 cells/mm3 and 1857 CD8 cells/mm*. Tests for rheumatoid factor, antinuclear antibodies, and anti-Ro and anti-La antibodies were all negative. Arterial blood gas analysis showed a P02 of 68 m m Hg and a P c o 2 of 35 m m Hg. Minor salivary gland biopsy showed distinct lymphocytic foci consistent with Sjogren syndrome. His histocompatibility type was H L A - D R 5 . A chest roentgenogram showed bilateral interstitial infiltrates, and an open lung biopsy showed lymphocytic interstitial pneumonitis. A n upper endoscopy and biopsy showed diffuse gastric infiltration by T lymphocytes. Because of the generalized infiltrative nature of his disorder, he was treated with chlorambucil, with total resolution of parotid enlargement and pulmonary and gastric infiltrates within 3 months. He continues on this therapy 18 months later. Patient 5 A 41-year-old black homosexual man presented with a 6-month history of massive bilateral parotid gland enlargement, severe dryness of the mouth and eyes, exertional dyspnea, fevers, and weight loss of 4.5 kg. Physical examination showed massively enlarged parotid glands bilaterally, cervical adenopathy, and fine endinspiratory crackles at both lung bases. Both ELISA and Western blot analysis showed HIV. Rheumatoid factor, antinuclear antibodies, and anti-Ro and anti-La antibodies were all absent. The patient had a leukocyte count of 5.7 X 10VL with 5 7 % lymphocytes. He had 260 C D 4 cells/mm3 and 2599 C D 8 cells/mm3. Histocompatibility type was H L A - D R 5 . A chest roentgenogram showed increased interstitial markings bilaterally. Arterial blood gas determination showed a P 0 2 of 60 m m Hg and a P c o 2 of 28 m m Hg. A gallium scan showed increased bilateral isotope uptake in the parotid, lacrimal, and submandibular glands and diffusely in the lung parenchyma. Minor salivary gland biopsy was consistent with Sjogren syndrome. Pulmonary function studies showed decreased lung volumes and severe diffusion abnormalities. A n open lung biopsy showed lymphocytic interstitial pneumonitis and parenchymal fibrosis. Despite an empiric 3-month course of prednisone, pulmonary function and clinical symptoms did not improve. Six months later, the patient developed pneumonococcal pneumonia. His respiratory status markedly deteriorated, and he required mechanical ventilation. Despite broad-spectrum antibiotic treatment and the absence of opportunistic infection, the patient died from respiratory failure. Patient 11 A 34-year-old Caucasian woman presented in 1984 with massive bilateral parotid enlargement and dry-

4

ness of the mouth. Rheumatoid factor, antinuclear antibodies, and anti-Ro and anti-La antibodies were all absent. A minor salivary gland biopsy showed distinct lymphocytic foci consistent with Sjogren syndrome. H L A typing showed DRw6, D R 1 . In 1988, the patient had applied for life insurance. Despite the absence of any risk factors, routine tests for H I V were positive by ELISA and Western blot analysis. The patient's leukocyte count was 5.1 X 10 9 /L with 4 5 % lymphocytes and T-lymphocyte studies showed 452 C D 4 cells/mm^ and 1550 C D 8 cells/mm*. She is otherwise well at present, with no opportunistic infections or malignancies. Patients and Methods Patients Seventeen patients (12 black, 2 Hispanic, and 3 Caucasian) were referred to the Bellevue, Manhattan Veterans Affairs, and Beth Israel hospitals and the Hospital for Joint Diseases for evaluation of sicca symptoms and parotid enlargement. Decreased lacrimation was measured by the Schirmer test; an abnormal result was less than 5 mm of filter paper moistened after 5 minutes. Keratoconjunctivitis was defined by abnormal Rose Bengal staining of the cornea. Xerostomia was defined clinically by subjective complaints of dry mouth; formal testing of salivary flow was not done. Pulmonary involvement was considered to be mild in the presence of radiographic changes or arterial oxygen saturation abnormalities without clinical symptoms and moderate to severe when progression to clinical symptoms or frank respiratory failure occurred. Serologic Studies Serum was tested for the presence of IgG antibodies to HIV using ELISA. Each serum sample was tested against both viral and control antigens. All positive serum samples were then tested for antibodies to HIV by Western blot analysis. Serum from seven patients was also tested for p24 antigen and for antibodies to human T lymphotrophic virus-I (HLTV-I) by ELISA. Serum samples were tested for rheumatoid factor by latex fixation. Titers equal to or greater than 1:40 were considered positive. Antinuclear antibodies were detected by indirect immunofluorescence using mouse liver as substrate, with dilutions equal to or greater than 1:20 considered positive. Antibodies to double-stranded DNA were detected by ELISA. Precipitating antibodies were determined using Ouchterlony double diffusion in agarose gel (0.6%) against extracts of bovine spleen (Ro/SSA) and rabbit thymus (La/SSB). Lymphocyte Phenotypic Analysis Peripheral blood lymphocyte subsets were analyzed in patients with diffuse infiltrative lymphocytosis syndrome, healthy controls, and HIV controls with AIDS-related complex or AIDS. Mononuclear cells from heparinized peripheral blood were separated by centrifugation on a Ficoll-Hypaque gradient (Pharmacia, Piscataway, New Jersey). CD4 and CD8 monoclonal antibodies, 91d6 and OKT8, were used in direct immunofluorescence conjugated with fluorescein isothiocyanate and biotinylated, respectively, or in indirect immunofluorescence with a fluorochrome-conjugated F(ab')2 fragment of rabbit anti-mouse Ig antibodies as described (11). Monoclonal antibodies against the CD29 and CD45R lymphocyte surface structures were directly conjugated with phycoerythrin or allophycocyanin, respectively. The percentages of double-labeled lymphocytes were determined in parallel by fluorescence microscopy and flow cytometry using a FACS 440 equipped with argon and helium

1 January 1990 • Annals ofInternal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

neon ion lasers and 5 parameter electronics (Becton-Dickinson, Mountain View, California). Lymphocytes were gated using combinations of low-angle forward scatter and 90 deg scatter defined by C D 3 and C D 14 reagents. Histopathology Minor salivary gland specimens (obtained by lower lip biopsy); specimens of parotid gland; and pulmonary, hepatic, renal, and gastric tissues were either fixed in formalin; sectioned serially at three levels and stained with hematoxylineosin; or snap-frozen, sectioned, and stained with immunoperoxidase-conjugated anti-CD4 and anti-CD8 antibodies. Minor salivary gland biopsy specimens were graded according to the criteria of Chisholm and Mason ( 1 2 ) . All of the tissues were stained and cultured for acid-fast bacilli and fungi.

H L A Typing a n d Nuclear Isotope Studies H L A typing was done on 12 black patients with diffuse infiltrative lymphocytosis syndrome and a matched control group of 45 black persons. Three other patients (2 Caucasian and 1 Hispanic patient) also had H L A typing. H L A studies were done with mononuclear and enriched B-cell preparations using standard two-stage microcytoxicity techniques and a panel of highly selected sera specific for all well-defined H L A - A , B, C, D R , and D Q antigens, as described ( 4 ) . T h e relative risk, as modified by Haldane ( 1 0 ) , and the Fisher exact probability were calculated. Patients were injected with 5 mCi [ 6 7 Ga] gallium citrate intravenously. Scanning of the body was done at 48 and 72 hours by a gamma camera. Table 1. Clinical Manifestations Patient

of the Diffuse Lymphocytosis

Results Patients Of the 17 patients, 15 were male and 2, female. Of the male patients, 12 were black, 1 Hispanic, and 2 Caucasian, and, of the female patients, 1 was Hispanic and 1 Caucasian. The age range was from 28 to 53 years. Eight of the patients were intravenous drug users, and 6 were homosexuals. T h e Caucasian patients (2 male and 1 female) were infected by heterosexual transmission. All of the 17 patients were positive for antibodies to H I V by E L I S A and by Western blot analysis. Six of the 7 tested patients lacked circulating p24 antigen, and none had antibodies against H T L V - I . A t the time of the initial study, none of the patients met criteria for A I D S ; and 14 met criteria for AIDS-related complex or stage 3B ( 1 3 ) , with fevers, generalized lymphadenopathy, and weight loss.

Glandular Features Bilateral parotid gland enlargement was present in all of the patients; it was massive in 12 patients and moderate in 5. Fourteen patients had xerostomia, and six had xerophthalmia diagnosed by the Schirmer test or had keratoconjunctivitis sicca determined by Rose Bengal staining of the cornea (Table 1). Gallium scanning was abnormal in all of 11 tested Syndrome

Bilateral XeroXerostomia Pulmonary Gastrointestinal Parotid phthalmia (LIP)* Enlargement

1

Massive

+

+

Mild

2

Massive

+

+

Moderate

Lymphocytic hepatitis

3

Massive

+

+

Severe

Gastric lymphocytic infiltration

4 5 6 7

Moderate Massive Moderate Massive

+ + — +

— + — —

Severe Severe

8

Massive

+

9 10 11 12

Moderate Massive Massive Massive

— + + +

— + —

13 14 15 16 17

Massive Massive Moderate Massive Moderate

+ + — + +

— — + — —

—

Mild

—

Severe

—

-

— — —

Lymphocytic hepatitis

— — —

Neurologic

Adenopathy

Other

VII cranial nerve palsy Bilateral V I I cranial nerve palsy; bilateral motor neuropathy; aseptic meningitis

+

Cryptococcal meningitis Anterior uveitis

+ — — — —

+ + + +

— — — —

VII cranial nerve palsy; aseptic meningitis Aseptic meningitis

+

Lymphocytic thymoma

— —

+ + — +

— — — — —

+ + + — —

Mild

— — Moderate

— Moderate

— — — _ —

+

— — _

Lymphocytic interstitial nephritis

— — — — —

*LIP == lymphocytic interstitial pneumonitis.

1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

5

Figure 1. Gallium scan showing increased uptake bilaterally in the lacrimal parotid, submandibular glands (arrows), and nasal mucosa.

patients. Nine patients had increased bilateral isotope uptake in the parotid, lacrimal, and submandibular glands. One patient showed bilateral uptake only in both parotids, and one patient only in the submandibular glands bilaterally. Increased uptake in the nasal mucosa was present in all of the patients (Figure 1). All of the 11 minor salivary gland biopsy samples that were obtained showed 2 or more discrete foci of at least 50 lymphocytes per 4 mm 2 of tissue or grade 4 according to the Chisholm and Mason criteria (12) (Figure 2 ) . Biopsy samples showed a spectrum from complete preservation of glandular architecture to atrophic duct epithelium, canal dilatation, and interstitial fibrosis. Examination of 4 minor salivary gland biopsy samples with immunoperoxidase-conjugated monoclonal antibodies against CD4 and CD8 showed the lymphocytic infiltrate in each to consist predominantly of CD8 positive T cells. Parotid gland biopsies in each of 9 patients, done to exclude the diagnosis of lymphoma, showed benign lymphoepithelial clusters. Extraglandular Features Fourteen of the patients had generalized adenopathy, with a predominance of bilateral cervical involvement. Ten patients had lung involvement, all with histologically proven lymphocytic interstitial pneumonitis (Table 1). N o histologic features characteristic of sarcoidosis, such as non-caseating granulomata, were seen in any tissue sample. All specimens were negative for acid-fast organisms or fungi. In four patients, the pulmonary involvement progressed to frank respiratory insufficiency needing therapy. Three patients have received high-dose corticosteroids, with improvement by both clinical and radiographic criteria evident in two of them. The third patient treated with prednisone had changes of extensive interstitial fibrosis as well as lym-

6

phocytic infiltration at presentation and progressed to end-stage pulmonary disease. A fourth patient, treated with chlorambucil, showed complete resolution of pulmonary infiltrates and disappearance of parotid enlargement. He remains entirely disease-free 18 months later and continues to receive chlorambucil. None of the patients treated with immunosuppressive therapy have yet developed opportunistic infections. Hepatomegaly and moderate elevations in transaminases and alkaline phosphatase occurred in two patients as a result of periportal CD8 lymphocytic infiltration of the liver. One patient had severe postprandial epigastric pain resulting from extensive gastric CD8 lymphocytic infiltration. Involvement of the nervous system was seen in four patients. Three patients had either unilateral or bilateral seventh nerve palsy, three had aseptic lymphocytic meningitis, and one developed a debilitating symmetric peripheral motor neuropathy. The AIDS dementia complex was not seen, and none of the patients with neurologic involvement had AIDS-related neurologic infections at the time. One patient developed a markedly enlarged thymus accompanying sicca symptoms and parotid enlargement. Thymic histology showed massive lymphocytic accumulation with no evidence of malignant cells. Removal of the hyperplastic thymus was associated with disappearance of parotid enlargement and resolution of sicca symptoms. Thymic enlargement was not seen on chest roentgenogram in the other patients. One patient had an anterior uveitis accompanying lymphocytic meningitis, and another patient developed moderate renal insufficiency as a result of biopsy-proven lymphocytic interstitial nephritis. Lymphocyte Phenotypic Analysis All 17 patients had leukocyte counts greater than 4.0 X 10 9 /L. Twelve of the patients had greater than 40% lymphocytes, and 15 had absolute C D 8 cell lymphocytosis. All patients had a C D 4 / C D 8 cell ratio of less than 1. Patients with diffuse infiltrative lymphocytosis syndrome had higher mean numbers of CD4 cells than those with AIDS-related complex or AIDS. An increased ratio of CD4 + C D 2 9 + cells to CD4 + C D 4 5 R + cells was seen in patients with diffuse infiltrative lymphocytosis syndrome, AIDS-related complex, and AIDS, compared with normal controls. Patients with diffuse infiltrative lymphocytosis syndrome had significantly higher numbers of CD8 + cells than other HIV-infected patients or healthy controls. This increase was mainly accounted for by a significant expansion of the CD8 + C D 2 9 + subset, which was the major lymphocyte population in these persons (Tables 2 and 3). Serologic and HLA Studies Polyclonal hypergammaglobulinemia was present in all of the patients. Three patients had positive rheumatoid factors, all at titers of less than 1:320. Two other patients had antinuclear antibodies, at titers less than

1 January 1990 • Annals ofInternal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

1:640. None of the patients had anti-Ro/SSA or antiLa/SSB antibodies. Of 12 black patients with diffuse infiltrative lymphocytosis syndrome, 10 were type HLA-DR5; whereas, only 13 of the 45 persons in a matched local control black population were type HLA-DR5. The estimated relative risk conferred by HLA-DR5 for diffuse infiltrative lymphocytosis syndrome in blacks infected with HIV is 10.1 ( P < 0.001). The Hispanic female patient was also type HLA-DR5, whereas the Caucasian female patient was type D R 1 , DRw6, and one Caucasian male patient was type HLA-DR2, DR3. None of the patients was type HLA-B8, and only two patients were type HLA-DR3. Figure 2. Minor salivary gland tissue stained with hematoxylin and eosin, showing two discrete lymphocytic foci (arrows), with relative preservation of glandular architecture.

Clinical Course The total number of patient-months from first detection of parotid gland enlargement to the end of the study period was 544. The median duration of followup per patient was 26 months (range, 6 to 72 months). Two patients have died, one from pneumococcal pneumonia complicating severe lymphocytic interstitial pneumonitis, and the other from incidental head trauma. Three patients have had complete resolution of sicca symptoms, parotid enlargement, and pulmonary infiltrates: one patient after treatment with chlorambucil, a second patient after thymectomy, and a third patient within 3 weeks of starting zidovudine. Two additional patients treated with zidovudine have had a diminuation in parotid mass. Two patients continue to receive corticosteroids for lymphocytic pneumonitis. Only one patient has developed an opportunistic infection, cryptococcal meningitis, and he is currently well on long-term fluconazole and zidovudine therapy. He is the only one of our patients with demonstrable circulating p24 antigen. Candidiasis and viral infections such as herpes zoster or cytomegaloviTable 2. Immunologic Patient

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

rus have not been encountered. None of the patients has developed Kaposi sarcoma or lymphoproliferative malignancy. Discussion We describe 17 patients infected with HIV who, in the setting of H L A - D R 5 , have developed a systemic lymphocytosis of C D 8 lineage T cells with clinically significant diffuse visceral infiltration. We have designated this manifestation of HIV infection "diffuse infiltrative lymphocytosis syndrome." The salivary and lacrimal glands as well as the lungs were most strikingly involved. Less frequently, lymphocytic infiltration of other tissues such as the liver, gastric mucosa, renal interstitium, and thymus was also seen. The most frequent clinical manifestations of diffuse infiltrative lymphocytosis syndrome were sicca symptoms and progressive dyspnea. Only 1 of our 17 patients has developed acquired immunodeficiency syndrome, and

Values

Total Leukocytes

Lymphocytes

X 1 M

%

4.4 9.3 9.2 5.1 5.7 4.8 7.3 8.6 4.6 8.5 5.1 7.6 8.2 5.1 5.0 6.9 10.0

60 43 31 56 57 35 25 45 26 60 45 33 41 68 66 50 51

C D 4 Cells*

C D 8 Cellst /mm3

< 370 409 427 357 260 212 NAJ 464 251 460 452 253 410 293 195 552 575

C D 4 / C D 8 Ratio

• 1954 2515 1857 1562 2599 1268 NA 1615 726 2300 1550 1215 1650 1785 1485 1839 3200

0.19 0.16 0.23 0.23 0.10 0.17 NA 0.29 0.35 0.20 0.29 0.21 0.25 0.16 0.13 0.30 0.18

* Normal = 390 to 1770/mm3. t Normal = 240 to 1200/mm3. JNA =• not available.

1 January 1990 • Annals ofInternal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

7

Table 3. Phenotypic Analysis of Lymphocyte Subsets: Expansion of the CD8+CD29+ Infiltrative Lymphocytosis Syndrome (DILS)* Variable

CD4 + CD4+CD29 + CD4 + CD45R+ (mean/mm3) ( mean/mm3) (mean/mm3)

Subset in Patients with the Diffuse

CD8 + CD8 + CD29 + CD8 + CD45R+ (mean/mm3) (mean/mm 3 ) ( mean/mm3)

n (£%) nf nnsitivf* ct*1fc}

11 I s€s KJ1 LsxS&ll'lY^'

DILS (n = 7) ARC (n = 7) AIDS (n = 5) Healthy controls (12 =

7)

339 217 59

175(52)tt 121(56) 33(56)

827

379(46)

67(20)tt 54(25) 14(23) 328(40)

•

^^ll&y

1556|t§ 568 622 513

767(50)tt§ 215(38) 251(40)

415(27) 213(38) 286(46)

267(52)

293(57)

* Values are mean cell number per cubic millimeter (mean/mm 3 ). AIDS = the acquired immunodeficiency syndrome; ARC = AIDS-related complex. t Significant difference between diffuse infiltrative lymphocytosis» syndrome and AIDS. % Significant difference between diffuse infiltrative lymphocytosisi syndrome and healthy controls. § Significant difference between diffuse infiltrative lymphocytosis syndrome and AIDS-related complex. Differences found to be significant at P < 0 . 0 1 by Wilcoxon rank sum test.

none has died as a result of opportunistic infection or malignancy. Salivary gland involvement in diffuse infiltrative lymphocytosis syndrome showed a spectrum from focal lymphocytic infiltration with preservation of glandular structures to total disruption of parenchymal architecture and diffuse fibrous replacement. These histologic features meet recommended criteria for the sicca syndrome (14). The sicca syndrome complex is most often seen in patients with primary Sjogren syndrome and in those with long-standing rheumatoid arthritis or some other rheumatic diseases. Emphasizing the diversity and changing spectrum of underlying disease processes, the sicca syndrome is also seen as a common manifestation of chronic graftversus-host disease (15) and in persons infected with HTLV-I (16). Each of these entities and HIV infection should, therefore, be considered in the differential diagnosis of patients presenting with the sicca syndrome (Table 4 ) . Classic Sjogren syndrome is characterized by a CD4-positive lymphocytic infiltration predominantly involving the salivary and lacrimal glands (17) and, less frequently, various extraglandular tissues (18). High titers of autoantibodies to Ro/SSA and La/SSB are present (15), and there is an association with HLA-DR2 or DR3 (19, 20) when primary and D R 4 when secondary to rheumatoid arthritis (19). In contrast, diffuse infiltrative lymphocytosis syndrome is characterized by C D 8 lymphocytic infiltration of the salivary glands, less lacrimal involvement, and a prominence of extraglandular visceral involvement. A paucity of autoantibodies is seen, and there is a strong association with HLA-DR5 among black individuals. C D 8 lymphocytic tissue infiltration is also seen in the sicca complex associated with HTLV-I infection (16) and chronic graft-versus-host disease (21). Autoantibodies have been reported to occur less frequently in men with primary Sjogren syndrome (22), although their HIV status was unknown, and to be absent from persons with the graft-versus-host disease (15). The commonest visceral manifestation in our patients was lymphocytic interstitial pneumonitis. Lymphocytic interstitial pneumonitis, sometimes with bilateral parotid gland enlargement, is frequently seen in

8

children infected with HIV (23), but has only occasionally been reported in adults ( 8 ) . Four patients in our study progressed to advanced pulmonary disease, and it appears that involvement of this organ system is the most serious complication of diffuse infiltrative lymphocytosis syndrome. The development and extent of the CD8 lymphocytic infiltration in the lungs, characteristic of lymphocytic interstitial pneumonitis (24), as well as that in parotid and glandular tissue, correlated directly with the absolute numbers of peripheral circulating CD8 cells. Visceral lymphocytic infiltration in diffuse infiltrative lymphocytosis syndrome may, therefore, be a direct consequence of the expanded population of circulating CD8 cells in these patients. CD8 lymphocytes cytotoxic to host cells infected with HIV have been shown both in the peripheral circulation (25) and in the pulmonary infiltrates of lymphocytic interstitial pneumonitis (26). Large amounts of gamma-interferon and other cytokines secreted by these activated CD8 cells (27) may be directly responsible for the tissue injury seen in diffuse infiltrative lymphocytosis syndrome . Although HIV has been cultured from bronchoalveolar lavage cells (28) and salivary glands (29), the additional role played by Epstein-Barr virus, cytomegalovirus, or other viruses in the development of the lymphocytic tissue infiltration remains to be studied. However, the response in three patients to zidovudine, an inhibitor of reverse transcriptase, suggests that HIV may be the dominant instigating factor. Corticosteroid or chlorambucil therapy aimed at lowering lymphocyte numbers, when instituted early, appeared to prevent progression to interstitial fibrosis. The use of these medications was not associated with any detrimental effects in our patients, in contrast to the adverse outcome of immunosuppressive therapy in patients with Reiter syndrome and HIV infection (30). Phenotypic analysis of peripheral blood lymphocytes was done to determine whether particular subpopulations are selectively expanded in patients with diffuse infiltrative lymphocytosis syndrome. Of particular interest are the changes in the functionally distinct subsets, present in both the CD4 and CD8 lymphocyte populations. These changes are recognized by monoclonal antibodies directed to the T200 leukocyte

1 January 1990 • Annals ofInternal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

common antigen structures designated CD45R and the /3 chain of fibronectin-binding structures in the VLA system designated CD29. Although CD45R-positive and CD29-positive lymphocytes were initially described as two distinct populations (31), more recent evidence suggests that CD45R-positive lymphocytes are naive cells in a single lineage that, on antigenic stimulation, become memory cells and express CD29 (32). Patients with diffuse infiltrative lymphocytosis syndrome showed a marked expansion of the CD8 + C D 2 9 + population compared with other patients infected with HIV. The expression of CD29 molecules and perhaps other homing receptors by the CD8 lymphocytes may lead to tissue infiltration by preferentially directing these cells to target tissues that contain high viral antigenic loads and large amounts of the appropriate accessory molecule ligands. Mice transgenic for the HTLV-I transactivating gene tax show high expression of the virally encoded protein within salivary gland epithelial cells and prominent epithelial cell proliferation (33). The ensuing salivary gland lymphocytic infiltration leads to histologic lesions indistinguishable from those seen in Sjogren syndrome. These observations suggest that lymphocytic infiltration of the salivary glands in diffuse infiltrative lymphocytosis syndrome may arise by either of two mechanisms: the first requiring MHC-restricted recognition of viral proteins expressed by epithelial cells and the second involving retrovirally mediated transactivation of endogenous genes that may be involved in the cell surface expression of adhesion molecule ligands. Furthermore, these observations raise the possibility that gene transactivation and aberrant expression of endogenous proteins by salivary gland epithelium may be the common underlying mechanism leading to lymphocytic tissue infiltration in the sicca syndrome. CD8 lymphocytes that are CD29 positive have recently been shown to suppress HIV replication in huTable 4. Contrasting Features of Diseases Associated Variable

Extraglandular manifestations

Infiltrative lymphocytic phenotype Autoantibodies

H L A association

Sjogren Syndrome

mans and simian immunodeficiency virus (SIV) in monkeys (34, 35). The mechanism is unclear but appears to require cell to cell interaction and to be MHC restricted. These findings suggest that patients with diffuse infiltrative lymphocytosis syndrome may selectively expand a population of C D 8 cells that suppresses viral replication. Indeed, preliminary attempts to isolate HIV from peripheral blood mononuclear cells in three of four patients with diffuse infiltrative lymphocytosis syndrome have proved very difficult, with first detection of reverse transcriptase activity in culture supernatants between days 45 and 60 (Croxson S, Miller L. Unpublished data). A protective mechanism against retroviral disease by specific MHC class II alleles has recently been shown in mice infected with murine leukemia virus (36). The strong association seen between HLA-DR5 and black patients with diffuse infiltrative lymphocytosis syndrome raises the intriguing possibility that the presence of a particular MHC class II allele confers, in some persons infected with HIV, the capability to markedly expand a population of CD8 lymphocytes that suppresses a viral replication. Whether this putative immune recognition event, presumably involving DR5 and a CD4 T lymphocyte, occurs at the level of antigen presentation or T-cell repertoire selection remains to be elucidated. The recent preliminary observation that all four of the DR5 patients studied by the polymerase chain reaction method to sequence their D R allele exhibit the same uncommon DR5 JVM subtype emphasizes the role played by a specific M H C allele in the development of diffuse infiltrative lymphocytosis syndrome (37). Together, these results suggest that certain MHC alleles may be critically involved in a host immune response that may influence the clinical manifestations and outcome of HIV infection. Acknowledgments: The authors thank Dr. Anne Jackson of the Becton Dickinson Corp. for providing anti-CD29 and anti-CD45R monoclonal antibodies; Drs. A. Lichtbroun and B. Alpert-Pura for making their

with the Sicca Chronic GraftVersusHost Disease

Syndrome* HTLV-I Infection

Diffuse Infiltrative Lymphocytosis Syndrome (HIV Infection)

Infrequent

Prominent

Prominent

Prominent

May have pulmonary, gastrointestinal, renal, and neurologic involvement CD4

Cutaneous, gastrointestinal, and pulmonary involvement

Pulmonary involvement and myelopathy

Pulmonary, gastrointestinal, and neurologic involvement

CD8

CD8

CD8

High frequency rheumatoid factor ANA Anti-Ro/SSA Anti-La/3SB

Absent

Unknown

B8; D R 2 , DR3; D R 4 (rheumatoid arthritis)

None

Unknown

Low frequency rheumatoid factor ANA Absent Anti-Ro/SSA Anti-La/SSB DR5

* HIV = human immunodeficiency virus; A N A = antinuclear antibody.

1 January 1990 • Annals ofInternal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017

patients available; Jeanne Dalton and Richard Perdue for flow cytometry and immunophenotyping; and Lillian Richman for secretarial assistance. Grant Support: Supported in part by NIH grants AR-35626 and AI19411. Requests for Reprints: Silviu Itescu, MD, Institute of Molecular Immunology, Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003. Current Author Addresses: Drs. Itescu, Brancato, Solomon and Winchester: Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003. Dr. Buxbaum: New York Veterans Affairs Medical Center, 408 First Avenue, New York, NY 10010. Dr. Gregersen: North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. Dr. Rizk: New York University Medical Center, 550 First Avenue, New York, NY 10016. Dr. Croxson: Cellular Bio-Reference Laboratory, 481-B Edward Ross Drive, Elmwood Park, NJ 07407. References 1. Lane HC, Fauci AS. Immunologic abnormalities in the acquired immune deficiency syndrome. Ann Rev Immunol. 1985;3:477-500. 2. Enlow RW, Nunez-Roldan A, LoGalbo P, Mildvan D, Mathur U, Winchester RJ. Increased frequency of HLA-DR5 in lymphadenopathy stage of AIDS [Letter]. Lancet. 1983;2:51-2. 3. Friedman-Kien AE, Laubenstein LJ, Rubinstein P, et al. Disseminated Kaposi's sarcoma in homosexual men. Ann Intern Med. 1982;96:693-700. 4. Mann DL, Murray C, Yarchoan R, Blattner WA, Goedert JJ. HLA antigen frequencies in HIV-1 seropositive disease-free individuals and patients with AIDS. J Acquir Immune Defic Syndr. 1988; 1:137. 5. Steel CM, Ludlam CA, Beatson D, et al. HLA haplotype A l B8 DR3 as a risk factor for HIV-related disease. Lancet. 1988;2:1185-8. 6. Zolla-Pazner S, Des Jarlais DC, Friedman SR, et al. Nonrandom development of immunologic abnormalities after infection with human immunodeficiency virus: implications for immunologic classification of the disease. Proc Natl Acad Sci USA. 1987;84:5404-8. 7. Guillon JM, Fouret P, Mayaud C, et al. Extensive T8-positive lymphocytic visceral infiltration in a homosexual man. Am J Med. 1987;82:655-61. 8. Solal-Celigny P, Couder LJ, Herman D, et al. Lymphoid interstitial pneumonitis in acquired immunodeficiency syndrome-related complex. Am Rev Respir Dis. 1985;131:956-60. 9. Itescu S, Brancato LJ, Winchester R. A sicca syndrome in HIV infection: association with HLA-DR5 and CD8 lymphocytosis. Lancet. 1989;2:466-8. 10. Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet. 1956;20:309-11. 11. Winchester RJ, Ross GD. Methods for enumerating cell population by surface markers using conventional microscopy. In: Rose N, Friedman H, Fahey JL, eds. Manual of Clinical Laboratory Immunology. Washington, DC: American Society for Microbiology; 1986;212-25. 12. Chisholm DM, Mason DK. Labial salivary gland biopsy in Sjogren's disease. / Clin Pathol. 1968;21:656-60. 13. Haverkos HW, Gotlieb MS, Killen JY, Edelman R. Classification of HTLV-IH/LAV-related diseases [Letter]. / Infect Dis. 1985;152:1095. 14. Greenspan JS, Daniels TE, Talal N, Sylvester RA. The histopathology of Sjogren's syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol. 1974;37:217-29. 15. Moutsopoulos HM, Chused TM, Mann DL, et al. Sjogren's syndrome (sicca syndrome): current issues. Ann Intern Med. 1980;92:212-26.

10

16. Vernant JC, Buisson G, Magdeleine J, et al. T-lymphocytic alveolitis, tropical spastic paresis, and Sjogren syndrome [Letter]. Lancet. 1988;1:177. 17. Adamson TC 3d, Fox RI, Frisman DM, Howell FV. Immunohistologic analysis of lymphoid infiltrates in primary Sjogren's syndrome using monoclonal antibodies. J Immunol. 1983;130:203-8. 18. Talal, N. Sjogren's syndrome. In: Rose NR, Mackay IR, eds. The Autoimmune Diseases. New York: Academic Press; 1985; 145-59. 19. Mann DL, Moutsopoulos H. HLA DR alloantigens in different subsets of patients with Sjogren's syndrome and in family members. Ann Rheum Dis. 1983;42:533-6. 20. Manthorpe R, Teppo AM, Bendixen G, Wegelius O. Antibodies to SS-B in chronic inflammatory connective tissue diseases. Relationship with HLA-Dw2 and HLA-Dw3 antigens in primary Sjogren's syndrome. Arthritis Rheum. 1982;25:662-7. 21. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjogren's syndrome. Proposed criteria for classification. Arthritis Rheum. 1986;29:577-85. 22. Molina R, Provost TT, Arnett FC, et al. Primary Sjogren's syndrome in men. Clinical, serologic, and immunogenetic features. Am J Med. 1986;80:23-31. 23. Pahwa S, Kaplan M, Fikrig S, et al. Spectrum of human T-cell lymphotropic virus type III infection in children. JAMA. 1986;255:2299-305. 24. Gartner S, Markovits P, Markovits D, Kaplan MH, Gallo RC, Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986;233:215-9. 25. Walker BD, Chakrabarti S, Moss B, et al. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature. 1987;328:345-8. 26. Plata F, Autran B, Martins LP, et al. AIDS virus-specific cytotoxic T lymphocytes in lung disorders. Nature. 1987;328:348-51. 27. Johnson, H. Mechanism of interferon gamma production and assessment of immunoregulatory properties. Lymphokines. 1985;11:33-46. 28. Venet AD, Clavel F, Israel-Biet D, et al. Lung in acquired immune deficiency syndrome: infectious and immunological status assessed by bronchoalveolar lavage. Bull Eur Physiopathol Respir. 1985;21:533-43. 29. Lecatsas A, Houff S, Macher A, et al. Retrovirus-like particles in salivary glands, prostate and testes of AIDS patients. Proc Soc Exp Biol Med. 1985;178:653-5. 30. Winchester R, Bernstein DH, Fischer HD, Enlow R, Solomon G. The co-occurrence of Reiter's syndrome and acquired immunodeficiency. Ann Intern Med. 1987;106:19-26. 31. Morimoto C, Letvin NL, Boyd AW, et al. The isolation and characterization of the human helper inducer T cell subset. / Immunol. 1985;134:3762-9. 32. Serra HM, Krowka JF, Ledbetter JA, Pilarski LM. Loss of CD45R (Lp220) represents a post-thymic T cell differentiation event. J Immunol. 1988;140:1435-41. 33. Green JE, Hinrichs SH, Vogel J, Jay G. Exocrinopathy resembling Sjogren's syndrome in HTLV-1 tax transgenic mice. Nature. 1989;341:72-4. 34. Walker CM, Moody DJ, Stites DP, Levy JA. CD8 + lymphocytes can control HIV infection in vitro by suppressing viral replication. Science. 1986;234:1563-6. 35. Tsubota H, Lord CI, Watkins Dl, Morimoto C, Letvin NL. A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. / Exp Med. 1989;169:1421-34. 36. Vasmel WL, Zijlstra M, Radaszkiewicz T, Leupers CJ, de Goede RE, Melief CJ. Major histocompatibility complex class II-regulated immunity to murine leukemia virus protects against early T- but not late B-cell lymphomas. / Virol. 1988;62:3156-66. 37. Itescu S, Brancato L, Gregersen PK, et al. Diffuse infiltrative CD8 lymphocytosis in HIV infection is associated with a particular subtype of HLA-DR5 [Abstract]. Clin Res. 1989;37:412A.

1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1

Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19695/ by a University of California San Diego User on 06/24/2017