Pediatric Annals

Genetic Predisposition to Autoimmune Disorders

Walter L Henley, MD

Abstract

Patients with autoimmune disorders frequently have family members with similar or other autoimmune disorders. Attempts are being made to relate this phenomenon to the major histocompatibility complex (MHC).

All individuals bear one major blood type- Type O, A, B or AB - and have antibodies to the non-self erythrocytes. A more specific self-antigen system for each individual has been recognized, initially on leukocytes; it, therefore, has been given the name "histocompatible leukocyte antigen" (HLA).

The HLA antigens that appear on all nucleated cells are controlled by genes in the MHC on the short arm of chromosome number 6. (This is where genes that control some components of the complement system are also located.) The HLA genes presently identified are HLA-A, HLA-B, HLA-C and HLA-D,andacloselyassociated(Drelated) HLA-DR that may represent an additional MHC locus. Their relative positions are schematically represented in Figure 1. Many alíeles are recognized for each of the HLA genes. There are at least 20 HLA-A alleles; over 40 HLA-Bs, 8 HLA-Cs, 12 HLA-Ds, and 10 HLA-DR alíeles to date (Table 1). Each individual inherits one set of MHC genes from each parent and the genotype can then be assessed by the antigens expressed on nucleated cells, i.e. the phenotype. H L ?-typing of H LA-A, B, C and DR is done with sera of individuals who have been exposed to antigens other than their own, and to which antibodies were produced (such as patients who have had many transfusions, and multipregnant mothers). HLADR is present mostly on B cells, but can be found on T cells and MNPs. HLA-D is more difficult to determine because identification requires the process of mixed lymphocyte culture - a cell-to-cell reaction where the cell being typed is incubated with a cell of an HLA-D type presumed to be different, which has been irradiated or treated with mitomycin. The cell to be typed, if truly different, reacts to the cell bearing the foreign HLA-D alíele and multiplies in mixed lymphocyte culture.1

HLA-typing is of importance in organ transplantation; the greater the number of compatible antigens between donor and recipient, the greater the likelihood of a successful graft; of all the HLA types, HLA-D appears most important.

HLA-typing has made it possible to correlate the presence of specific antigens with similar disorders in family members and unrelated individuals. Thus, some HLA types have been linked to a susceptibility to acquire certain diseases, whereas others were recognized as associated with disorders of autoimmunity (Table 2). Although currently only in theoretical stages, these associations are certain to be of practical importance in the future:2 Individuals bearing a certain HLA phenotype, or cells from a particular tissue or organ from such an individual, may be more vulnerable to damage by an infectious agent (?viral) while other antigens may actually be protective.* Juvenile insulin-dependent diabetes melHtus, which has been shown to occur after a viral infection involving cells of the islets of the pancreas, 3i4 may be an example of such predisposition. The prevalence of individuals with certain HLA types in disorders of autoimmunity has been most dramatically documented between patients with ankylosing spondylitis and HLAB27. Spondyloarthritis involves the joints of spine and hip, but may be associated with rheumatoid factor negative peripheral rheumatoid arthritis.! Other rheumatic disorders associated with an increased prevalence of HLA-B27 are Reiter's syndrome, arthritis with inflammatory bowel disease, arthritis subsequent to Salmonella, Shigelia or Yersinia (and perhaps also Campylobacter and viral) infection, and especially pauciarticular arthritis associated with iridocyclitis. There are also relationships between various arthritides and HLA-DR4and DR5.5-8

1. Bach FH and Van Rood JJ. The major histocompatibility complexGenetics and Biology. NewEngl…

Patients with autoimmune disorders frequently have family members with similar or other autoimmune disorders. Attempts are being made to relate this phenomenon to the major histocompatibility complex (MHC).

All individuals bear one major blood type- Type O, A, B or AB - and have antibodies to the non-self erythrocytes. A more specific self-antigen system for each individual has been recognized, initially on leukocytes; it, therefore, has been given the name "histocompatible leukocyte antigen" (HLA).

The HLA antigens that appear on all nucleated cells are controlled by genes in the MHC on the short arm of chromosome number 6. (This is where genes that control some components of the complement system are also located.) The HLA genes presently identified are HLA-A, HLA-B, HLA-C and HLA-D,andacloselyassociated(Drelated) HLA-DR that may represent an additional MHC locus. Their relative positions are schematically represented in Figure 1. Many alíeles are recognized for each of the HLA genes. There are at least 20 HLA-A alleles; over 40 HLA-Bs, 8 HLA-Cs, 12 HLA-Ds, and 10 HLA-DR alíeles to date (Table 1). Each individual inherits one set of MHC genes from each parent and the genotype can then be assessed by the antigens expressed on nucleated cells, i.e. the phenotype. H L ?-typing of H LA-A, B, C and DR is done with sera of individuals who have been exposed to antigens other than their own, and to which antibodies were produced (such as patients who have had many transfusions, and multipregnant mothers). HLADR is present mostly on B cells, but can be found on T cells and MNPs. HLA-D is more difficult to determine because identification requires the process of mixed lymphocyte culture - a cell-to-cell reaction where the cell being typed is incubated with a cell of an HLA-D type presumed to be different, which has been irradiated or treated with mitomycin. The cell to be typed, if truly different, reacts to the cell bearing the foreign HLA-D alíele and multiplies in mixed lymphocyte culture.1

HLA-typing is of importance in organ transplantation; the greater the number of compatible antigens between donor and recipient, the greater the likelihood of a successful graft; of all the HLA types, HLA-D appears most important.

HLA-typing has made it possible to correlate the presence of specific antigens with similar disorders in family members and unrelated individuals. Thus, some HLA types have been linked to a susceptibility to acquire certain diseases, whereas others were recognized as associated with disorders of autoimmunity (Table 2). Although currently only in theoretical stages, these associations are certain to be of practical importance in the future:2 Individuals bearing a certain HLA phenotype, or cells from a particular tissue or organ from such an individual, may be more vulnerable to damage by an infectious agent (?viral) while other antigens may actually be protective.* Juvenile insulin-dependent diabetes melHtus, which has been shown to occur after a viral infection involving cells of the islets of the pancreas, 3i4 may be an example of such predisposition. The prevalence of individuals with certain HLA types in disorders of autoimmunity has been most dramatically documented between patients with ankylosing spondylitis and HLAB27. Spondyloarthritis involves the joints of spine and hip, but may be associated with rheumatoid factor negative peripheral rheumatoid arthritis.! Other rheumatic disorders associated with an increased prevalence of HLA-B27 are Reiter's syndrome, arthritis with inflammatory bowel disease, arthritis subsequent to Salmonella, Shigelia or Yersinia (and perhaps also Campylobacter and viral) infection, and especially pauciarticular arthritis associated with iridocyclitis. There are also relationships between various arthritides and HLA-DR4and DR5.5-8

Figure 1. Scheme of the major histocompatibility complex (schematic): Sites of genes controlling HLA antigens and some components of complement system. Reproduced with permission of Williams and Wilkins. Co., Baltimore.

Figure 1. Scheme of the major histocompatibility complex (schematic): Sites of genes controlling HLA antigens and some components of complement system. Reproduced with permission of Williams and Wilkins. Co., Baltimore.

Table

TABLE 1HLA ANTIGEN SPECIFICITIES*

TABLE 1

HLA ANTIGEN SPECIFICITIES*

Table

TABLE 2AUTOIMMUNE DISORDERS AND HLA ALLELES

TABLE 2

AUTOIMMUNE DISORDERS AND HLA ALLELES

Table

TABLE 3DISEASES LINKED TO GENES IN MHC

TABLE 3

DISEASES LINKED TO GENES IN MHC

Immune disorders of the gastrointestinal tract, such as gluten-sensitive enteropathy (coeliac sprue), chronic active hepatitis, and dermatitis herpetiformis are associated with HLA-B8 and Dw3/DR3. Endocrinopathies like Graves* disease, Addison's disease and insulin-dependent diabetes are associated with the same HLA allleles as are myasthenia gravis and Sjogren's syndrome5-7 (Table 2).

It is interesting that HLA-B8 is associated both in patients with chronic active hepatitis and dermatitis herpetiformis. The former appears to result from inadequate antibody production to hepatitis B virus surface antigen. On the other hand, patients with dermatitis herpetiformis are reported to have diminished T-y (T1) cells, with increased immunoglobulin production and increased circulating immunecomplexes, particularly IgA complexes.8 Moreover, associations have also been reported between the presence of HLA-B8- Dw3/DR3 and toxic reactions to both gold and D-penicillamine used in the treatment of rheumatoid disorders.7,8

The associations with the D/ DR genetic loci of many of the above disorders have been more recently reported and may be stronger than the earlier linkages reported with HLA-B genes. There appears to exist linkage disequilibrium between the D/ DR and B genes (particularly the B8 and B27 alleles) leading to their frequent association. The role of these genetic factors in the pathogenesis of autoimmune disorders is under active investigation and remains to be definitively established.2

Autoimmune disorders are associated with certain HLA types. Some diseases known to pediatricians are definitely linked to genes in the major histocompatibility complex. Examples are 21-hydroxylase deficiency leading to congenital adrenal hyperplasia, immunodeficiency and autoimmune disorders due to deficiencies in complement components C2 and C4, and probably C6 and C8 deficiencies which are associated with recurrent neisserial infection (Table 3).

REFERENCES

1. Bach FH and Van Rood JJ. The major histocompatibility complexGenetics and Biology. NewEngl J Med 295:806-813, 872-878, 927-936, 1976.

2. McDevitt H. Regulation of the immune response by the major histocompaiibilily system. N Engl J Med 303:1514-1517, 1980.

3. Yoon JW, et al. Virus-induced diabetes mellitus. N Engl J Med 300:1173-1179, 1979.

4. Cahill GF Jr. and McDevitt HO- Insulin-dependent diabetes mellitus: The initial lesion. N Engl J Med 304:1454-1465, 1981.

5. Gru met FC. HLA and disease association. Transplant Proc 9:1839-1844, 1977.

6. Stastny P. Association of Ihe B-cell alloaniigen DRw4 with rheumatoid arthritis. N Engl J Med 296:869-871, 1978.

7. Schaller JG and Hansen JA. HLA relationships Io disease. Hosp Pract 16:41-49, 1981.

8. Panayi GS, Wooley P, Batchelor JR. Genetic basis of rheumatoid disease. HLA antigens, disease manifestations, and toxic reactions to drugs. Br Med J 2:1326-1328, 1978.

9. Lawley TJ. et al. Defective Fc-receptor functions with the H LA-B8- DRw3 haplotype. N Engl J Med 304:185-192. 1 9Kl.

10. Winchester RJ and Kunkel HG. The human Ia system. In: Advances in Immunology. Dixon FJ and Kunkel HG (eds). New York: Acad Pr, 1979.

11. Ungar B, et at. HLA-DR patterns in pernicious anemia. Br Med J 282:768770, 1981.

TABLE 1

HLA ANTIGEN SPECIFICITIES*

TABLE 2

AUTOIMMUNE DISORDERS AND HLA ALLELES

TABLE 3

DISEASES LINKED TO GENES IN MHC

10.3928/0090-4481-19820401-07

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