> Skip repeated content

HSS Manual Ch. 5 - Immunogenetic Aspects Of Rheumatic Diseases

From the HSS Manual of Rheumatology and Outpatient Orthopedic Disorders

Image - Photo of Allan Gibofsky, MD
Allan Gibofsky, MD
Attending Physician, Hospital for Special Surgery
Professor of Medicine and Public Health, Weill Cornell Medical College

The efforts of numerous investigators during the past three decades have resulted in the recognition of a major histocompatibility complex (MHC) 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, it was recognized 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. Although it is recognized that many of the rheumatic disease may occur as a result of multiple genetic factors, the strongest influences have been with the HLA genes of the MHC. This chapter reviews the basic concepts of immunogenetics, emphasizing the potential significance of the HLA system antigens in clinical rheumatology.


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

  1. Loci definition. Multiple closely linked loci have been defined by gene mapping techniques and their products recognized by a combination of serologic and DNA typing methods. (A complete listing of the several hundred recognized alleles defined for the six loci can be found at http://www.anthonynolan.org/ ). These genes have been functionally assigned to several classes:
    1. Class I includes the products of the HLA- A, B, and C series.
    2. Class II includes the products of the HLA- DR, DP and DQ series.
    3. Class III has recently been described and consists of the genes for various peptide transporters (TAP), proteosome subunits (LMP) , and other proteins involved in autoimmunity (DM, DO).

       Initial studies directed toward the development of serologic methods for the detection of HLA-D antigens 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 of the mother with paternal antigens during pregnancy or in the sera of renal transplant recipients who became immunized against non-matching antigens present on the homograft. These human Ia antigens are highly polymorphic and have certain allo-antigenic specificities related closely to HLA alleles. The gene products of the HLA-D region appear to be highly complex, polymorphic, and not yet fully defined. Each product consists of a non-covalently 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; (b) DQ molecules; and (c) DP molecules 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.

  2. 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.


  1. 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 chronic arthritis). This knowledge could facilitate the search for possible etiologic agents and confirm or refute the following suggested mechanisms for HLA and disease associations:
    1. The HLA antigen may be structurally similar to the antigenic component of an infectious agent.
    2. The HLA antigen may be part of a neo-antigen, formed in combination with an infectious agent.
    3. The HLA antigen may be a receptor for an infectious or environmental toxin.
    4. There may be linkage disequilibrium (i.e. the genes are located so closely together on the same chromosome that they are usually inherited together) between alleles at a particular locus and the HLA antigen associated with that disease (e.g. HLA-A3 and idiopathic hemochromatosis).

  2. Ankylosing Spondylitis. The most significant association of any HLA antigen occurs in this disease. Between 85% and 90% of Caucasian patients have HLA-B27, which seems to be a marker for spondylitis 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-DR association has been recognized, which suggests that susceptibility to ankylosing spondylitis may involve mechanisms different from those involved in the other rheumatic diseases such as rheumatoid arthritis.

  3. Reactive Arthritis (formerly Reiter Syndrome). Nearly 80% of Caucasian patients with the classic triad of manifestations (i.e. arthritis, urethritis, conjunctivitis) have the antigen B27. This antigen is also seen in slightly lower frequency in forms of the syndrome with fewer than three findings. 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.

  4. Rheumatoid arthritis (RA). HLA-DR4 (in particular the subtype, DR4B1*01) has been reported in 60% to 80% of Caucasian 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.

  5. Systemic lupus erythematosus (SLE). Both HLA-DR antigens DR2 and DR3 have been found to be increased in Caucasian patients with SLE. In addition, genes on other chromosomes have also been implicated in increasing susceptibility to SLE (Chapter 30). This immunogenetic diversity would support the clinical variability 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.

  6. Sjögren Syndrome. Caucasian patients with primary Sjögren syndrome show a strong association with HLA-DR3. Of interest was the report that HLA-DR4 (in particular, the subtype DR4B1*01) is increased in frequency in patients with Sjögren syndrome associated with a connective tissue disorder such as RA or SLE, which no doubt reflects the high incidence of RA seen in this population.

  7. 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.

  8. 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.

  9. Behçet Disease. The HLA antigen Bw51 is increased in Caucasian patients with this condition. The association is even more significant in Asian and Asian-American patients.

  10. Lyme Disease. HLA-DR2 and HLA-DR4 are increased in Caucasian patients with this disorder.

  11. C2 Deficiency. The gene coding for the second component of complement is located on chromosome 6 and is part of the major histocompatibility complex 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) have been reported.

  12. 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.

  13. Juvenile Idiopathic Arthritis. HLA-B27 has been reported in 40% of patients with combined pauciarticular and axial disease. Associations with HLA-DR5 and HLA-DR8 have also been reported.

    Need Help Finding a Physician?

    Call us toll-free at:

    Related Professional Content

    Conditions & Treatments

    adult child
    Select A Body Part
    Conditions: Adult head Conditions: Adult spine Conditions: Adult shoulder Conditions: Adult elbow Conditions: Adult hand Conditions: Adult hip Conditions: Adult knee Conditions: Adult ankle Conditions: Adult head Conditions: Adult full body Conditions: Child spine Conditions: Child elbow Conditions: Child hip Conditions: Child hand Conditions: Child knee Conditions: Child ankle Conditions: Child full body

    Conditions A-Z
    A B C D E F G H I
    J K L M N O P Q R
    S T U V W X Y Z