J Chron Dis, Vol. 31, pp. 307-311 @ Pergamon Press Ltd. 1978. Printed
0021-9681/78/0501-0307
!SO2.00/0
in Great Britain
Editorial THE MAJOR HISTOCOMPATIBILTTY AND DISEASE MICHAEL
Medical Wilshire
H. DTETZ and RODNEY
COMPLEX
BLUESTONE
and Research Services, Veterans Administration, Wadsworth Hospital Center, and Sawtelle Boulevards, Los Angeles, CA 90073 and Department of Medicine, UCLA School of Medicine, Los Angeles.CA 90024, U.S.A. (Received9 March 1977)
GLOSSARY Allele-one of two or more possible forms of a gene. Alloantigen--polypeptide recognized as foreign in the induction of graft rejection between genetically dissimilar individuals within a species. Alloantisera-(Alloantibody~immunoglobulins directed against alloantigens. Allogeneic-dcscriptive term describing cells or individuals within a species differing genetically and antigenically. B-cell-‘Bursal equivalent’or ‘bone-marrow derived’ lymphocyte involved in immunoglobulin synthesis. H-2-the major histocompatibility complex of the mouse. HLA-the major histocompatibility complex of man. Major histocompatibility complex (MHCtsegment of chromosome carrying genetIc Information coding for cell surface proteins involved in graft acceptance or rejection. Product-molecular expression, in part polypeptide, of a gene. Specificity-an MHC allele identified by histocompatibility typing. Syngeneicdescriptive term describing cells or individuals withm a species identical genetically and antigenically. T-cell -Thymus derived lymphocyte.
THE
MAJOR
HISTOCOMPATIBILITY
COMPLEX
AND
DISEASE
THE ASSOCIATIONSbetween
the major histocompatibility complex (MHC)* and certain human diseases have stimulated investigators to postulate basic pathophysiologic mechanisms of these diseases on a molecular level. As of 1976, associations with HLAA or B specificities have been confirmed for approximately thirty clinical syndromes [l]. Since that time, other associations between HLA-D or B-cell alloantigens (antigens expressed primarily on B-cells and monocytes) have been uncovered. The disease susceptibility factors are probably polygenic. Many of these syndromes are acquired and chronic in nature and hence the role of HLA in disease is of direct interest to clinicians caring for affected individuals. Multiple sclerosis, juvenile diabetes mellitus, coeliac disease, and dermatitis herpetiformis are just a few examples of diseases *A glossary
has been included
to which the reader may quickly refer for terminology 307
which is unfamiliar.
MICHAEL H. DIETZ
308
and
RODNEY BLUESTONE
Centromere
1
I
D
e
1 C
I
t
j---No.
6 Chromosome
A
I
(a)
HLA System
Centromere ErllXlome Region
KABJECSGD I
I
I H-2
WC’s
OF MAN MD
System
(b)
MOUSE
Figure
la.
HLA superpenoma pictured on Chromosome 6. Arrow indicates that genetic information at the B locus is translated into a minabrane associated protein, which my be detected through alloantisera.
Figure
lb.
H-2 supergenome
of
PIouse.
associated with certain HLA specificities [2]. The clinician caring for patients with various rheumatologic disorders must be aware of the strong associations between ankylosing spondylitis and B-27 [3,4], Reiter’s Syndrome and B-27 [S], and associations between other HLA specificities and Sjogren’s syndrome, systemic lupus erythematosis, Behcet’s disease, psoriasis, complement deficiencies and rheumatoid arthritis. The HLA system is located on the No. 6 chromosome. It is composed of four loci, D,B,C,A, each having multiple alleles or specificities (see Fig. la) The gene products of the A and B loci, the classical transplantation antigens, are cell membrane glycoproteins found on nucleated cells and platelets, and are noncovalently linked to b2microglobulin, although the /3,-microglobulin is not coded for by the HLA complex [6]. Along with C locus antigens, A and B antigens are identified by serologic methods. D locus antigens and their relationships to B-cell alloantigens are not as well characterized. The D locus antigens are identified through mixed leucocyte culture (MLC). B-cell alloantigens are identified through antisera prepared by absorbing out antibodies to A,B, and C determinants. In addition to these loci, others coding for various components of the complement system and minor blood groups are in this vicinity on chromosome No. 6. A comprehensive overview has been recently published [7]. Research into the biologic roles played by HLA products is in its infancy, but over the past 10 yr investigators have uncovered some of the roles MHC products may play in other species. Perhaps these can serve as models for the human system.
The major histocompatibility complex and disease
309
Laboratory animals, notably the mouse and guinea pig, have afforded investigators unique opportunities in the study of the structure and functions of the MHC through genetic and immunologic manipulations. The MHC of the mouse is referred to as H-2. It is on chromosome No. 17 and divided into regions K, I, S, G and D. The I region contains subregions which include I-A, I-B, I-J, I-E, and I-C [8]. (See Fig. 16.) H-2K and H-2D products may be defined serologically (HLA-A, B, and C are analogous). I region derived antigens and products may be defined through MLC, tumor virus susceptibility, allograft rejection, innune response gene properties, or alloantisera. I region determined antigens identified by alloantisera are termed Ia antigens. These Ia antigens are preferentially expressed on the surface of B-cells and macrophages (B-cell alloantisera are probably analogous). The S region carries information coding for certain serum proteins, some of which are related to levels of hemolytic complement. Certainly the prime function of the MHC in nature is not one mediating allogeneic graft rejection. Much of the data in the experimental animal points to the MHC as playing a significant role in general immunological surveillance, involving primarily the afferent limb (‘recognition’) but also the efferent limb (‘effector’) of the immune system. The ability of an organism to recognize an antigen and then synthesize specific antibody against it has been termed ‘immune response’. Through the immunization of experimental animals with synthetic polypeptides, investigators have determined that part of the directive to develop a secondary antibody response and cellular immunity towards these antigens resides in the I region of H-2 [9, lo]. These directives arise from so-called immune response (Ir) genes. Furthermore, H-2 products, usually I region associated, play roles in macrophage-lymphocyte interactions [l l-131, T-cell and B-cell cooperation [14] and the production of soluble suppressor [15] and enhancing factors [16] which alter immunologic reactivity. H-2 products may also play a role in the action of ‘killer’ cells directed against syngeneic cells which have been chemically modified [17] or infected with virus [18]. This is an exciting experimental model for so-called human ‘autoimmune’ diseases. Evidently the MHC of the experimental animal encompasses genes whose products probably play significant roles in determining how it may respond to a variety of antigens in its environment. It seems likely that similar genes may also exist in man and play a role in disease susceptibility. These ‘disease susceptibility genes’ may be those coding for the classical transplantation antigens or they may be genes in the vicinity of the genes coding for transplantation antigens. The concepts of genetic proximity are defined according to Mendelian principles. When two different loci recombine less frequently than predicted, a state of genetic linkage exists. Genetic dysequilibrium, occuring between genes of linked loci, is said to be present during the time it takes a newly introduced gene, a mutation, to appear in combination with all possible genes
[191. From animal models these possible mechanisms for the operation of ‘disease susceptibility genes’ in man are suggested: (1) Abnormal antibody responses, either too high or too low. There is some evidence suggesting Ir-like genes in man [20-221. (2) Abnormal immunocompetent cell interactions. Recently there have been studies showing decreased responses to mitogens among individuals sharing certain specificities [23]. (3) The MHC serving as a receptor for viruses. Although there is evidence of
310
MICHAELH. DIETZand RODNEYBLUETONE
genetically determined virus susceptibility, the receptor hypothesis is unsubstantiated in experimental system [24]. (4) Alteration of the MHC by an environmental agent, so that antigenic determinants previously recognized as ‘self are later recognized as foreign, and (5) finally, another attractive theorey suggests molecular mimicry between HLA antigens and foreign proteins. The host, in responding to the foreign protein, also attacks itself because of polypeptide similarities between its own cell surface and the foreign protein. There is scant evidence for this and it comes mainly from HLA research
WI.
Clinically, histocompatibility typing may identify populations at risk for developing certain HLA-associated chronic disease syndromes. As specific environmental agents triggering disease are identified, perhaps the role of the clinician will be to offer means where these agents are avoided, or once encountered, rapidly eliminated. A potential example of this may be the clinician’s rapid treatment of bacillary dysentery or nongonococcal urethritis in an individual carrying the B-27 antigen. Finally, as the body of knowledge relating to HLA and disease grows, the appropriate opportunities may develop for genetic counselling. REFERENCES 1. Ryder LP, Svejgaard A: In: Report from the HLA and disease registry of Copenhagen. Published by authors, 1976 2. Dausset J, Svejgaard A: HLA and disease. INSERM (Paris), 1976 3. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288 :704-06, 1973 4. Brewerton DA, Hart FD, Nicholls A et al.: Ankylosing spondylitis and HL-A W27. Lancet 1:904-07, 1973 5. Morris R, Metzger A, Bluestone R, Terasaki P: HLA W27-A clue to the diagnosis and pathogenesis of Reiter’s syndorme. N Engl J Med 290:554-556, 1974 6. Crumpton MJ, Snary D: Isolation and structure of human histocompatibility (HLA) antigens. In: Contemporary topics of molecular immunology 6:52-82, 1977 I. Bach FH, van Rood JJ: The major histocompatibility complex. N Engl J Med 295:806-13,872-77, 927-36,1976 8. Murphy DB, Okumura K, Herzenberg LA, Herzenberg LA, McDevitt HO: Selective expression of separate I-region loci in Functionally different lymphdcyte subpopulations. Cold Spring Harbor Symp. Quant Biol41: 497-504,1976 9. McDevitt HO, Chinitz A: Genetic control of the antibody response and histocompatibility (H-2) type. Science, NY 175:1207-08, 1969 immune response genes. Science, NY 10. Benacerraf B, McDevitt HO: Histocompatibility-linked 163:273-79, 1972 11. Pierce CE, Kapp JA, Benacerraf B: Regulation of the H-2 gene complex of macrophage-lymphoid cell interactions in secondary antibody responses in vitro. J Exp Med 144: 371-81, 1976 12. Shevach E: The role of the macrophage in genetic control of the immune response. Fedn Proe 35:2048-2052,1976 13. Thomas DW, Yamashita U, Shevach EM: Nature of the antigenic complex recognized by T lymphocytes. IV. Inhibition of antigen-specific T cell proliferation by antibodies to stimulator macrophage Ia antigens. J Immunol119:223-26, 1977 14. Katz DH: Genetic controls and cellular interactions in antibody formation. Hosp Pratt 12(2):85-99, 1977 15. Tada T, Taniguchi M: Characterization of the antigen-specific suppressive T cell factor with special reference to the expression of I region gene complex in immune response. pp. 513-534, In: Katz DH, Benacerraf B, (Ed) The role of products of the histocompatibility gene complex in immune responses. Academic Press, New York, 1976 16. Katz DH. Armerding D, Eshar 2: Histocompatibility gene products as mediators of lymphocyte interactions. pp. 541-552, In: Katz DH, Benacerraf B, (Ed) The role of products of the histocompatibility gene complex in immune responses. Academic Press, New York, 1976 17. Shearer GM: Cell-mediated cytotoxicity to trinitrophenyl-modified syngeneic lymphocytes. Eur J Immunol4:527-33,1974
The major histocompatibility
18. 19. 20. 21. 22. 23. 24.
25.
complex
and disease
311
Zinkernagel RM, Doherty PC: Restriction of in vitro T cell mediated cytotoxicity in lymphocytic choriomeniningitis within a syngeneic or semiallogeneic system. Nature, Lond 248:701-02,1974 Chase GA: Genetic linkage, gene-locus assignment, and the association of alleles with diseases. Transplantation Proceedings 9:i67-71, 1977 Marsh DB. Bias WB. Hsu SH et al.: Association of the HL-A7 cross-reacting arouu with a snecific reaginic aniibody response in allergic man. Science, NY 179:691-93, 1973 - _ _ Spencer MJ, Cherry JD, Terasaki PI: HL-A antigens and antibody response after influenza vaccination. N Engl J Med 294:13-16,1976 Greenberg LJ, Gray ED, Yunis EJ: Association of HL-A5 and immune responsiveness in tlitro to streptococcal antigens. J Exp Med 141:935-43,1975 Michalski JP, McCombs C, Fye KH et a[.: Impaired lymphocyte reactivity and HLA-B8 in Sjogren’s syndrome. (Abst.) Clin Res 25:119A, 1977 Zinkemagel RM, Oldstone MBA: Cells that express viral antigens but lack H-2 determinants are not lysed by immune thymus-derived lymphocytes but are lysed by other antiviral immune attack mechanisms. Proc Nat1 Acad Sci, USA 73:3666-70,1976 Ebringer A, Cowling P, Ngwa Suh N et al.: Crossreactivity between Klebsiella aerogenes species and B27 lymphocyte antigens as a aetiological factor in ankylosing spondylitis (Abst.) p. 27, In: Dausset J. Svejgaard A: HLA and disease. INSERM (Paris) 1976
0021-9681/78/0501-0307
!SO2.00/0
in Great Britain
Editorial THE MAJOR HISTOCOMPATIBILTTY AND DISEASE MICHAEL
Medical Wilshire
H. DTETZ and RODNEY
COMPLEX
BLUESTONE
and Research Services, Veterans Administration, Wadsworth Hospital Center, and Sawtelle Boulevards, Los Angeles, CA 90073 and Department of Medicine, UCLA School of Medicine, Los Angeles.CA 90024, U.S.A. (Received9 March 1977)
GLOSSARY Allele-one of two or more possible forms of a gene. Alloantigen--polypeptide recognized as foreign in the induction of graft rejection between genetically dissimilar individuals within a species. Alloantisera-(Alloantibody~immunoglobulins directed against alloantigens. Allogeneic-dcscriptive term describing cells or individuals within a species differing genetically and antigenically. B-cell-‘Bursal equivalent’or ‘bone-marrow derived’ lymphocyte involved in immunoglobulin synthesis. H-2-the major histocompatibility complex of the mouse. HLA-the major histocompatibility complex of man. Major histocompatibility complex (MHCtsegment of chromosome carrying genetIc Information coding for cell surface proteins involved in graft acceptance or rejection. Product-molecular expression, in part polypeptide, of a gene. Specificity-an MHC allele identified by histocompatibility typing. Syngeneicdescriptive term describing cells or individuals withm a species identical genetically and antigenically. T-cell -Thymus derived lymphocyte.
THE
MAJOR
HISTOCOMPATIBILITY
COMPLEX
AND
DISEASE
THE ASSOCIATIONSbetween
the major histocompatibility complex (MHC)* and certain human diseases have stimulated investigators to postulate basic pathophysiologic mechanisms of these diseases on a molecular level. As of 1976, associations with HLAA or B specificities have been confirmed for approximately thirty clinical syndromes [l]. Since that time, other associations between HLA-D or B-cell alloantigens (antigens expressed primarily on B-cells and monocytes) have been uncovered. The disease susceptibility factors are probably polygenic. Many of these syndromes are acquired and chronic in nature and hence the role of HLA in disease is of direct interest to clinicians caring for affected individuals. Multiple sclerosis, juvenile diabetes mellitus, coeliac disease, and dermatitis herpetiformis are just a few examples of diseases *A glossary
has been included
to which the reader may quickly refer for terminology 307
which is unfamiliar.
MICHAEL H. DIETZ
308
and
RODNEY BLUESTONE
Centromere
1
I
D
e
1 C
I
t
j---No.
6 Chromosome
A
I
(a)
HLA System
Centromere ErllXlome Region
KABJECSGD I
I
I H-2
WC’s
OF MAN MD
System
(b)
MOUSE
Figure
la.
HLA superpenoma pictured on Chromosome 6. Arrow indicates that genetic information at the B locus is translated into a minabrane associated protein, which my be detected through alloantisera.
Figure
lb.
H-2 supergenome
of
PIouse.
associated with certain HLA specificities [2]. The clinician caring for patients with various rheumatologic disorders must be aware of the strong associations between ankylosing spondylitis and B-27 [3,4], Reiter’s Syndrome and B-27 [S], and associations between other HLA specificities and Sjogren’s syndrome, systemic lupus erythematosis, Behcet’s disease, psoriasis, complement deficiencies and rheumatoid arthritis. The HLA system is located on the No. 6 chromosome. It is composed of four loci, D,B,C,A, each having multiple alleles or specificities (see Fig. la) The gene products of the A and B loci, the classical transplantation antigens, are cell membrane glycoproteins found on nucleated cells and platelets, and are noncovalently linked to b2microglobulin, although the /3,-microglobulin is not coded for by the HLA complex [6]. Along with C locus antigens, A and B antigens are identified by serologic methods. D locus antigens and their relationships to B-cell alloantigens are not as well characterized. The D locus antigens are identified through mixed leucocyte culture (MLC). B-cell alloantigens are identified through antisera prepared by absorbing out antibodies to A,B, and C determinants. In addition to these loci, others coding for various components of the complement system and minor blood groups are in this vicinity on chromosome No. 6. A comprehensive overview has been recently published [7]. Research into the biologic roles played by HLA products is in its infancy, but over the past 10 yr investigators have uncovered some of the roles MHC products may play in other species. Perhaps these can serve as models for the human system.
The major histocompatibility complex and disease
309
Laboratory animals, notably the mouse and guinea pig, have afforded investigators unique opportunities in the study of the structure and functions of the MHC through genetic and immunologic manipulations. The MHC of the mouse is referred to as H-2. It is on chromosome No. 17 and divided into regions K, I, S, G and D. The I region contains subregions which include I-A, I-B, I-J, I-E, and I-C [8]. (See Fig. 16.) H-2K and H-2D products may be defined serologically (HLA-A, B, and C are analogous). I region derived antigens and products may be defined through MLC, tumor virus susceptibility, allograft rejection, innune response gene properties, or alloantisera. I region determined antigens identified by alloantisera are termed Ia antigens. These Ia antigens are preferentially expressed on the surface of B-cells and macrophages (B-cell alloantisera are probably analogous). The S region carries information coding for certain serum proteins, some of which are related to levels of hemolytic complement. Certainly the prime function of the MHC in nature is not one mediating allogeneic graft rejection. Much of the data in the experimental animal points to the MHC as playing a significant role in general immunological surveillance, involving primarily the afferent limb (‘recognition’) but also the efferent limb (‘effector’) of the immune system. The ability of an organism to recognize an antigen and then synthesize specific antibody against it has been termed ‘immune response’. Through the immunization of experimental animals with synthetic polypeptides, investigators have determined that part of the directive to develop a secondary antibody response and cellular immunity towards these antigens resides in the I region of H-2 [9, lo]. These directives arise from so-called immune response (Ir) genes. Furthermore, H-2 products, usually I region associated, play roles in macrophage-lymphocyte interactions [l l-131, T-cell and B-cell cooperation [14] and the production of soluble suppressor [15] and enhancing factors [16] which alter immunologic reactivity. H-2 products may also play a role in the action of ‘killer’ cells directed against syngeneic cells which have been chemically modified [17] or infected with virus [18]. This is an exciting experimental model for so-called human ‘autoimmune’ diseases. Evidently the MHC of the experimental animal encompasses genes whose products probably play significant roles in determining how it may respond to a variety of antigens in its environment. It seems likely that similar genes may also exist in man and play a role in disease susceptibility. These ‘disease susceptibility genes’ may be those coding for the classical transplantation antigens or they may be genes in the vicinity of the genes coding for transplantation antigens. The concepts of genetic proximity are defined according to Mendelian principles. When two different loci recombine less frequently than predicted, a state of genetic linkage exists. Genetic dysequilibrium, occuring between genes of linked loci, is said to be present during the time it takes a newly introduced gene, a mutation, to appear in combination with all possible genes
[191. From animal models these possible mechanisms for the operation of ‘disease susceptibility genes’ in man are suggested: (1) Abnormal antibody responses, either too high or too low. There is some evidence suggesting Ir-like genes in man [20-221. (2) Abnormal immunocompetent cell interactions. Recently there have been studies showing decreased responses to mitogens among individuals sharing certain specificities [23]. (3) The MHC serving as a receptor for viruses. Although there is evidence of
310
MICHAELH. DIETZand RODNEYBLUETONE
genetically determined virus susceptibility, the receptor hypothesis is unsubstantiated in experimental system [24]. (4) Alteration of the MHC by an environmental agent, so that antigenic determinants previously recognized as ‘self are later recognized as foreign, and (5) finally, another attractive theorey suggests molecular mimicry between HLA antigens and foreign proteins. The host, in responding to the foreign protein, also attacks itself because of polypeptide similarities between its own cell surface and the foreign protein. There is scant evidence for this and it comes mainly from HLA research
WI.
Clinically, histocompatibility typing may identify populations at risk for developing certain HLA-associated chronic disease syndromes. As specific environmental agents triggering disease are identified, perhaps the role of the clinician will be to offer means where these agents are avoided, or once encountered, rapidly eliminated. A potential example of this may be the clinician’s rapid treatment of bacillary dysentery or nongonococcal urethritis in an individual carrying the B-27 antigen. Finally, as the body of knowledge relating to HLA and disease grows, the appropriate opportunities may develop for genetic counselling. REFERENCES 1. Ryder LP, Svejgaard A: In: Report from the HLA and disease registry of Copenhagen. Published by authors, 1976 2. Dausset J, Svejgaard A: HLA and disease. INSERM (Paris), 1976 3. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288 :704-06, 1973 4. Brewerton DA, Hart FD, Nicholls A et al.: Ankylosing spondylitis and HL-A W27. Lancet 1:904-07, 1973 5. Morris R, Metzger A, Bluestone R, Terasaki P: HLA W27-A clue to the diagnosis and pathogenesis of Reiter’s syndorme. N Engl J Med 290:554-556, 1974 6. Crumpton MJ, Snary D: Isolation and structure of human histocompatibility (HLA) antigens. In: Contemporary topics of molecular immunology 6:52-82, 1977 I. Bach FH, van Rood JJ: The major histocompatibility complex. N Engl J Med 295:806-13,872-77, 927-36,1976 8. Murphy DB, Okumura K, Herzenberg LA, Herzenberg LA, McDevitt HO: Selective expression of separate I-region loci in Functionally different lymphdcyte subpopulations. Cold Spring Harbor Symp. Quant Biol41: 497-504,1976 9. McDevitt HO, Chinitz A: Genetic control of the antibody response and histocompatibility (H-2) type. Science, NY 175:1207-08, 1969 immune response genes. Science, NY 10. Benacerraf B, McDevitt HO: Histocompatibility-linked 163:273-79, 1972 11. Pierce CE, Kapp JA, Benacerraf B: Regulation of the H-2 gene complex of macrophage-lymphoid cell interactions in secondary antibody responses in vitro. J Exp Med 144: 371-81, 1976 12. Shevach E: The role of the macrophage in genetic control of the immune response. Fedn Proe 35:2048-2052,1976 13. Thomas DW, Yamashita U, Shevach EM: Nature of the antigenic complex recognized by T lymphocytes. IV. Inhibition of antigen-specific T cell proliferation by antibodies to stimulator macrophage Ia antigens. J Immunol119:223-26, 1977 14. Katz DH: Genetic controls and cellular interactions in antibody formation. Hosp Pratt 12(2):85-99, 1977 15. Tada T, Taniguchi M: Characterization of the antigen-specific suppressive T cell factor with special reference to the expression of I region gene complex in immune response. pp. 513-534, In: Katz DH, Benacerraf B, (Ed) The role of products of the histocompatibility gene complex in immune responses. Academic Press, New York, 1976 16. Katz DH. Armerding D, Eshar 2: Histocompatibility gene products as mediators of lymphocyte interactions. pp. 541-552, In: Katz DH, Benacerraf B, (Ed) The role of products of the histocompatibility gene complex in immune responses. Academic Press, New York, 1976 17. Shearer GM: Cell-mediated cytotoxicity to trinitrophenyl-modified syngeneic lymphocytes. Eur J Immunol4:527-33,1974
The major histocompatibility
18. 19. 20. 21. 22. 23. 24.
25.
complex
and disease
311
Zinkernagel RM, Doherty PC: Restriction of in vitro T cell mediated cytotoxicity in lymphocytic choriomeniningitis within a syngeneic or semiallogeneic system. Nature, Lond 248:701-02,1974 Chase GA: Genetic linkage, gene-locus assignment, and the association of alleles with diseases. Transplantation Proceedings 9:i67-71, 1977 Marsh DB. Bias WB. Hsu SH et al.: Association of the HL-A7 cross-reacting arouu with a snecific reaginic aniibody response in allergic man. Science, NY 179:691-93, 1973 - _ _ Spencer MJ, Cherry JD, Terasaki PI: HL-A antigens and antibody response after influenza vaccination. N Engl J Med 294:13-16,1976 Greenberg LJ, Gray ED, Yunis EJ: Association of HL-A5 and immune responsiveness in tlitro to streptococcal antigens. J Exp Med 141:935-43,1975 Michalski JP, McCombs C, Fye KH et a[.: Impaired lymphocyte reactivity and HLA-B8 in Sjogren’s syndrome. (Abst.) Clin Res 25:119A, 1977 Zinkemagel RM, Oldstone MBA: Cells that express viral antigens but lack H-2 determinants are not lysed by immune thymus-derived lymphocytes but are lysed by other antiviral immune attack mechanisms. Proc Nat1 Acad Sci, USA 73:3666-70,1976 Ebringer A, Cowling P, Ngwa Suh N et al.: Crossreactivity between Klebsiella aerogenes species and B27 lymphocyte antigens as a aetiological factor in ankylosing spondylitis (Abst.) p. 27, In: Dausset J. Svejgaard A: HLA and disease. INSERM (Paris) 1976
