The RBC ABO surface antigens are found in most tissues except the central nervous system (CNS). Some of the other RBC antigens, such as the P system, may occur in some locations outside the RBCs. White blood cells also possess a complex antigen group that is found in other tissues; more specifically, in nucleated cells. This is called the human leukocyte-A (HLA) system and is found in one site (locus) on chromosome number 6. Each locus is composed of four subloci. Each of the four subloci contains one gene. Each sublocus (gene) has multiple alleles (i.e., a pool of several genes), any one of which can be selected as the single gene for a sublocus. The four major subloci are currently designated A, B, C, and D. There is possibly a fifth sublocus, designated DR (D-related), either close to the D locus or part of it.

HLA-A, B, and C are known as class I antigens. They have similar structure, including one polypeptide heavy chain, and can be identified using standard antiserum (antibody) methods. The class II antigen HLA-D is identified by the mixed lymphocyte culture test in which reagent lymphocytes with HLA-D antigen fail to stimulate proliferation of patient lymphocytes when patient lymphocytes havethe same HLA-D antigen but will stimulate proliferation if the patient HLA-D antigens are not compatible. HLA-DR is classified as a class II antigen with a structure that includes two polypeptide heavy chains. It includes a group of antigens found on the surface of B-lymphocytes (B antigen) and also in certain other cells such as monocytes but not in most T-lymphocytes. HLA-DR is currently tested for by antibody methods using patient lymphocytes and antibody against DR antigen (microcytotoxicity test). Two other antigen groups, MB and MT, which are closely associated with HLA-DR, have been described.

The four subloci that form one locus are all inherited as a group (linked) in a manner analogous to the Fisher-Race theory of Rh inheritance. Again analogous to Rh, some HLA gene combinations are found more frequently than others.

The HLA system has been closely identified with tissue transplant compatibility to such a degree that some refer to HLA as histocompatibility leukocyte-A. It has been shown that HLA antigens introduced into a recipient by skin grafting stimulate production of antibodies against the antigens that the recipient lacks, and that prior sensitization by donor leukocytes produces accelerated graft rejection. In kidney transplants from members of the same family, transplant survival was found to correlate with closeness of HLA matching between donor and recipient. On the other hand, there is evidence that HLA is not the only factor involved, since cadaver transplants frequently do not behave in the manner predicted by closeness of HLA typing using HLA-A and B antigens. There is some evidence that HLA-D, DR, and MB antigens may also be important in renal transplant compatibility.

Platelets contain HLA antigens, and patients who receive repeated transfusions of platelets may become refractory to such transfusions due to immunization against HLA antigens. Transfusion of HLA-A and B compatible platelets improves the success rate of the platelet units. However, about one third of platelet transfusion units containing well-matched HLA-A and B platelets will not be successful once the patient is sufficiently immunized.

HLA antigens on each chromosome are inherited as a unit in a mendelian dominant fashion. Therefore, HLA typing has proved very useful in paternity case investigations.

Besides their association with immunologic body defenses, certain HLA antigens have been found to occur with increased frequency in various diseases. The B27 antigen is associated with so-called rheumatoid arthritis (RA) variants (Chapter 23). In ankylosing spondylitis, Reiter’s syndrome, and Yersinia enterocolitica arthritis, HLA-B27 occurs in a very high percentage of cases. The incidence of HLA-B27 in ankylosing spondylitis is 90%-95% (range, 83%-96%) in Europeans and approximately50% in African Americans. In Reiter’s syndrome the incidence is 80%-90% (range, 63%-100%) in Europeans and approximately 35% in African Americans. In juvenile rheumatoid, psoriatic, and enteropathic (ulcerative colitis and Crohn’s disease) arthritis, the incidenceof HLA-B27 depends on the presence of spondylitis or sacroiliitis. In all RA-variant patients, those with spondylitis or sacroiliitis have B27 in more than 50% of cases (some report as high as 70%-95%); without clinical disease in these locations, B27 is found in less than 25%. Increased frequency of the B27 antigen was also reported in close relatives of patients with ankylosing spondylitis.

An increased incidence of certain other HLA antigens has been reported in celiac disease (HLA-B8), chronic active hepatitis, and multiple sclerosis (as well as in various other diseases) but with lesser degrees of correlation than in the RA variants. The significance of this is still uncertain, and verification is needed in some instances.