13. | Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)

Chapter 6 Immunogenetic Aspects of Rheumatic Diseases

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 6 Immunogenetic Aspects of Rheumatic Diseases

Allan Gibofsky

Immunogenetic nomenclature
Immunogenetic nomenclature
Disease associations
	Ankylosing spondylitis
	Reiter's syndrome
	Rheumatoid arthritis (RA)
	Systemic lupus erythematosus (SLE)
	Sicca syndrome
	Psoriatic arthritis
	Inflammatory bowel disease (IBD)
	Behet's disease
	Lyme disease
	C2 deficiency
	Rheumatic fever
	Juvenile rheumatoid arthritis

The efforts of numerous investigators during the past three decades have resulted in the recognition of a major histocompatibility complex in humans consisting of the alleles of at least seven closely linked loci on the short arm of autosomal chromosome 6. The antigens that the genes of this region code for were first detected on white blood cells and were therefore originally referred to as human leukocyte antigens (HLA). Initially, these antigens interested primarily transplantation physicians, as similarity between donor and recipient seemed to influence allograft survival; soon, however, the hypothesis was advanced that certain clinical conditions might be associated with one or more antigens of this system. A large number of diseases have been studied, and individual or combinations of antigens have appeared with greater frequency than would be expected in the normal population. This increase is particularly true for rheumatic diseases and related syndromes with features of altered immunoreactivity, where, as will be discussed, the strongest and most significant associations have been demonstrated. This chapter reviews the basic concepts of immunogenetics, emphasizing the potential significance of the HLA system antigens in clinical rheumatology.

I. Immunogenetic nomenclature

Gene. Segment of DNA that directs the synthesis of a polypeptide chain or protein.
Allele. Alternative form of the same gene, resulting from mutation or duplication.
Locus. The position of a gene on any given chromosome.
Genotype. The genetic composition of an individual.
Phenotype. The observed expression of the genotype.
Haplotype. Closely linked loci, transmitted as a unit from each parent; two haplotypes constitute the genotype.
Allo-antigen. Product of the A, B, C, or DR, DP, or DQ loci; recognized on the cell surface by specific antibody.
Determinant. Product of the HLA-D locus; recognized by cell-cell interaction in the mixed lymphocyte culture technique.

II. Immunogenetic nomenclature

Loci definition. Seven closely linked loci, A, B, C, D, DR, DP, and DQ, were defined at the Ninth International Histocompatibility Workshop in 1984; the alleles of each are shown in Table 6-1. The products of the A, B, and C series are defined by using serologic reagents, most often with a lymphocytotoxicity assay.

Table 6-1. Complete listing of recognized serologic and cellular HLA specificities

The determinants of the D locus are defined by cell-cell interaction in the mixed lymphocyte culture.

Initial studies directed toward the development of serologic methods for the detection of HLA-D antigens have resulted in the recognition of several additional gene products, preferentially expressed on the surface of B lymphocytes. These B-cell antigens have extensive biologic and chemical homologies with the I-region antigens of the murine histocompatibility system and are therefore also referred to as Ia antigens. These Ia allo-antigens were primarily recognized with allo-antibodies that developed as a result of immunization with paternal antigens during pregnancy or in the sera of renal transplant recipients who became immunized against nonmatching antigens present on the homograft (see Table 6-1). These human Ia antigens are highly polymorphic and have certain allo-antigenic specificities related closely to HLA alleles. The studies from the Tenth International Histocompatibility Workshop indicate that the gene products of the HLA-D region appear to be highly complex, polymorphic, and not yet fully defined. Each product consists of a noncovalently associated combination of an alpha and a beta chain. The alpha and beta chains are substantially different from each other, and there is evidence for at least six alpha-chain genes and seven beta-chain genes, all in the HLA region. These genes appear to be arranged in subsets corresponding to three distinct products, all of which are class II molecules: (a) DR molecules, with homology to murine I-E antigens (one alpha and two or three beta chains); (b) DQ molecules, with homology to murine I-A antigens (two alpha and two beta chains); and (c) DP molecules, intermediate in structure between I-A and I-E (two alpha and two beta chains), which appear not to be serologically defined. The alpha- and beta-chain genes of each series' products are significantly more similar to each other than to genes of one of the other allelic series.
Genetics of inheritance. The antigens of this system are inherited in classic mendelian fashion. Unlike those phenotypic characteristics that exhibit dominant and recessive forms (e.g., eye color and ABO type), the HLA antigens are co-dominant; if a gene has been inherited from a parent, the corresponding HLA antigen will be expressed on the cell surface. Given the number of alleles at each locus, the number of possible phenotypic combinations is very large, indicating the enormous immunogenetic heterogeneity of an outbred population. Thus, the finding of an altered frequency of a particular antigen in a patient group is likely to prompt intense interest in the biologic role of this system in the regulation of the immune response and disease susceptibility.

III. Disease associations. Of the many conditions thus far investigated and shown to be associated with particular alleles of the HLA system, the rheumatic diseases have been the most important. Although the associations are high, they are neither absolute nor diagnostic; the presence of an antigen is not the sole factor in disease pathogenesis, for the antigen also occurs in disease-free persons.

Nevertheless, knowledge of the association may prove useful in permitting subdivisions of clinical groups within the larger population (e.g., pauciarticular juvenile rheumatoid arthritis). This knowledge could facilitate the search for possible etiologic agents and confirm or refute the following suggested mechanisms for HLA and disease associations:

The HLA antigen may be structurally similar to the antigenic component of an infectious agent.
The HLA antigen may be part of a neo-antigen, formed in combination with an infectious agent.
The HLA antigen may be a receptor for an infectious or environmental toxin.
There may be linkage disequilibrium with one or more immune response genes.

Ankylosing spondylitis. The most significant association of any HLA antigen occurs in this disease. Between 85% and 90% of white patients have HLA-B27, which seems to be a marker for seronegative axial arthropathy in this group.
Ethnic differences may be important as well, because the antigen occurs with different frequency in both patient and control nonwhite groups. The lower association in Pima Indians and American blacks, groups in which the disease itself is less frequent, would suggest that B27 is not involved directly in pathogenesis but rather may be linked to the predisposing gene. Thus far, no HLA-D or -DR association has been recognized, which suggests that susceptibility to ankylosing spondylitis may involve mechanisms different from those involved in the other rheumatic diseases.
Reiter's syndrome. Nearly 80% of white patients with the classic triad of symptoms have the antigen B27. This antigen is also seen in slightly lower frequency in incomplete forms of the syndrome. It has been suggested that the reactive arthritis seen following infection with Yersinia or Salmonella is comparable to the form of Reiter's syndrome following bacterial dysentery. In these conditions also, HLA-B27 is increased.
Rheumatoid arthritis (RA). The B lymphocyte allo-antigen HLA-DR4 has been reported in 60% to 80% of white patients with classic adult seropositive RA, in comparison with 24% to 28% of controls. In contrast, no significant HLA association has been detected in adult patients with clinically similar seronegative disease, which suggests that seronegative and seropositive RA may have a different immunogenetic basis.
Systemic lupus erythematosus (SLE). Both HLA-DR antigens DR2 and DR3 have been found to be increased in white patients with SLE. This immunogenetic diversity would support the clinical diversity seen in this disease. Some data have suggested that clinical subgroups of patients with SLE show an association with one or the other HLA-DR antigen (e.g., with DR3 in skin disease and with DR2 in vasculitis), but not necessarily with both.
Sicca syndrome. White patients with primary sicca syndrome show a strong association with HLA-DW3 and the related B-cell antigen HLA-DR3. Of interest was the report that HLA-DR4 is increased in frequency in patients with secondary sicca syndrome, which no doubt reflects the high incidence of RA seen in this population.
Psoriatic arthritis. The HLA antigens A26, B38, Cw6, DR4, and DR7 have been reported to be increased in patients with psoriatic arthritis. In addition, B2 has been reported to be increased in patients with axial skeletal disease. Different antigens have been associated with skin disease alone.
Inflammatory bowel disease (IBD). Patients with IBD and ankylosing spondylitis show an increased frequency of HLA-B27. No increase in the frequency of this antigen is seen in patients with enteropathic peripheral arthritis as a manifestation of IBD.
Behet's disease. The HLA antigen Bw51 is increased in white patients with this condition. The association is even more significant in Oriental patients.
Lyme disease. HLA-DR2 and HLA-DR4 are increased in white patients with this disorder , which results from a Borrelia bergdorferi spirochete transmitted by an Ixodes scapularis.
C2 deficiency. The gene coding for the second component of complement is located on chromosome 6 and is part of the major histocompatibility complex. Fu and associates have reported several family studies of patients with C2 deficiency and an SLE-like illness in whom the deficient C2 gene segregated with the same haplotype (A10-B18).
Rheumatic fever. In several groups of patients with this disease, a B-cell allo-antigen not related to HLA-D has been detected in virtually all patients tested . The relationship of this allo-antigen to other genes located within the major histocompatibility complex remains to be determined.
Juvenile rheumatoid arthritis. HLA-B27 has been reported in 40% of patients with combined pauciarticular and axial disease. Associations with the B-cell allo-antigens HLA-DR5 and HLA-DRw8 have also been reported.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders