L. A. Piccinini

Autoimmune thyroid disease and thyroid cell class II major histocompatibility complex antigens.

Differences in the immune response to antigenic stimuli, including thyroid autoantigens, have been linked to a group of genes known collectively as the Major Histocompatibility Complex (MHC), which in humans is referred to as the Human Leukocyte Antigen (HLA) complex (Benacerraf, 1981). These genes encode a series of polymorphic cell surface molecules; the class I, 11 & I11 antigens. Classically, class I antigens are expressed on all nucleated cells in the body and are recognized by cytotoxic and suppressor T cells. Class I1 antigens, however, are primarily restricted in their constitutive expression to cells of the immune system and are recognized by the T helper cell subset. Class I11 antigens represent components of the complement pathway. Theories on the aetiology of autoimmune thyroid disease have often invoked a ‘thyroid component’ to such immune responses, but the evidence has been indirect and usually in the form of inherited metabolic abnormalities present in the thyroid cell rather than an immunologically-defined antigen (Wick et al., 1982). However, recent studies on intrathyroidal lymphocyte function have demonstrated the potent role of thyroid antigenic stimulation within the target organ (Totterman et al., 1979; McLachlan et al., 1983; Londei et al., 1984). The finding of MHC class I1 antigens on the surface of the murine thyroid cell (Salamero et al., 1981), and later in human thyroid epithelium (Hanafusa et al., 1983), has focused attention on the generalized facilitation by MHC class I1 antigens in the development of thyroid autoimmunity. This review includes a basic introduction to the class I1 antigens and discusses our present understanding of their involvement in the development of human thyroid autoimmunity.

Role of MHC class II antigen expression in thyroid autoimmunity

Major histocompatibility complex (MHC) class I1 antigens are represented in man by the HLA-D region gene family which is composed of polymorphic genetic loci (DR, DP, and DQ) mapping to the short arm of chromosome 6, in mice by the Ia gene family on chromosome 17 (IA and IE), and in the rat by RTI.B, D, and H gene regions (FIG. l).’ The typical M H C class I1 antigen molecule is a heterodimer, consisting of an alpha (34-kd) and a beta (28-kd) glycopeptide chain that is linked noncovalently within the plasma membrane and is associated intracellularly with an invariant (33-kd) glycopeptide.* The genetic variation both within the human population and within different animal species a t the MHC class I1 region is largely attributable to the amino acid sequence differences within the first external domain of the polymorphic beta chain. Many studies have demonstrated the association between M H C genes, particularly those of class 11, and autoimmune thyroid disease in animals and humans’ (TABLE 1). The relative risk of autoimmune thyroid disease attached to any of these antigens (principally HLA-DR3 and DR5) in humans is low, and 30-50% of patients with disease do not express an associated HLA antigen. However, studies of HLA haplotypes within individual multiplex families of patients with autoimmune thyroid disease indicate that unique familial associations may be of primary importance: a fact that improved methods of HLA typing may detect in the general population. Similarly, particular murine and rat strains are known to be high or low immunoresponders to thyroid antigens, and this responsiveness has been linked to the M H C class I1 gene ~ o m p l e x . ~ * ~ In addition to these disease-specific relationships, particular HLA haplotypes have been associated with abnormal immune responsiveness of a nonantigen-specific nature. For example, normal HLA-DR3 individuals have less effective T-cell suppressor function than do non-DR3 normal^.^

Allospecific Dr Gene Expression on the Human Thyroid Cell

Human thyroid epithelial cells, stimulated with recombinant gamma interferon (IF) (100 U/ml), were HLA-DR typed by means of antibody-dependent, complement-mediated cytotoxicity. The thyroid cell lysis reaction patterns were found to be similar to those obtained with autologous peripheral B cells in four of five separate experiments. Since the cytotoxic reactions with thyroid cells were sometimes incomplete with many antisera, a two-color fluorescence technique was developed to measure the specificity of the antibody-dependent, complement-mediated lysis. Using constitutively HLA-D antigen-positive Raji B lymphoblastoid cells as controls, we showed that non-polymorphic HLA-D and HLA-DR determinants could be detected on the thyroid cell surfaces by this cell lysis approach. In addition, gamma IF stimulated thyroid cells from a DR3 positive individual were lysed to a significantly greater than unstimulated autologous thyroid cells with the use of a specific monoclonal antibody to HLA-DR3, thus confirming the original HLA typing studies. These data demonstrate, for the first time, that the expression of HLA-DR antigen on the surface of human thyroid cells is allospecific and may, therefore, play an important role in the immunopathology of autoimmune thyroid disease.

Regulation of HLA-DR Gene Expression in Cultured Human Thyroid Cells: A Role for Lectin, Gamma Interferon, and Cyclosporine

HLA Class II antigens (DR, DQ, and DP) are expressed primarily on the surface of the lymphocytes (B and activated T cells) and cells of the monocyte-macrophage lineage, but may also be expressed in a variety of tissues, in particular those which contain immune infiltration with local release of lymphokines (i.e., gamma interferon), which are potent inducers of Class II antigen expression. Immunofluorescence studies have demonstrated that although normal human thyroid tissue is negative for DR antigen, HLA-DR antigen is present in human thyroid cells in cases of autoimmune thyroid disease such as Graves’ hyperthyroidism (1,2). Furthermore, Class II HLA-DR antigen in normal thyroid cells is detected after exposure in vitro to lectin or gamma-interferon (1,3). Since Class II antigens are important in T cell amplification, antigen presentation and self-recognition (4), such quantitative differences in DR antigen expression in the thyroid may be involved in the control of thyroid autoimmunity. In order to further elucidate the role of Class II antigens in thyroid immunoregulation, we have studied HLA-DR antigen gene expression in a variety of cultured human thyroid cells.