ACP medicine, 3rd Edition


Adaptive Immunity: Histocompatibility Antigens and Immune Response Genes

Edgar Louis Milford M.D.1

Charles B. Carpenter M.D.2

1Associate Professor of Medicine, Harvard Medical School, Physician, Brigham and Women's Hospital

2Professor of Medicine, Harvard Medical School, Senior Physician, Brigham and Women's Hospital

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

July 2004

The major histocompatibility complex (MHC) was first appreciated in mice as a set of proteins, encoded by closely linked genes on chromosome 17, that serve as the major targets for rejection of skin grafts. Humans were subsequently shown also to have MHC antigens, which are homologous to those found in the mouse but are encoded in the human leukocyte antigen (HLA) region on the short arm of chromosome 6 [see Figure 1]. Initially, human MHC antigens could be defined only by use of sera from multiparous women who had mounted humoral immune responses against the paternally derived MHC antigens in their fetuses. The development of DNA-based methods for genotyping of individuals has permitted more extensive study of these extraordinarily polymorphic molecules. This chapter reviews the genetics and structure of the MHC, its function in the immune response, and its association with disease.


Figure 1. Loci of Major Histocompatibility Complex

The best-characterized loci of the human major histocompatibility complex (MHC), located in the HLA region of the short arm of chromosome 6, are depicted. Distances are shown in recombination units (centimorgans), as determined by crossover frequencies in family studies, and in kilobases, as determined by sequence analysis of fragments produced by DNAses having defined cleavage sites. MHC class II molecules are encoded in the HLA-DP, HLA-DQ, and HLA-DR genes, and MHC class I molecules are encoded by HLA-B, HLA-C, and HLA-A genes. A cluster of closely linked complement genes—C4, BF, and C2—lies in the center of the region. There are two structural genes for C4, interspersed with two genes for the adrenal enzyme 21-hydroxylase. Next is the heat shock protein gene,Hsp70, followed by the tumor necrosis factor (TNF) genes, A and B. The orientation of the complement cluster and the TNF cluster has not been established, but an expanded view of this area could be depicted as -(C4-210HA-C4B-210HB-BF-C2)-(HSP70)-(TNFA-TNFB).GLO is a marker gene for the enzyme glyoxylase. An expansion of the class II region is in the lower portion of the figure. Each class II molecule is a heterodimer of an α and a β chain, which are encoded in the A and B genes, respectively. Pseudogenes, which are not expressed on the cell surface, are shown in white boxes. HLA-DP and HLA-DQ have one expressed heterodimer, A1B1; HLA-DR has only one A chain but nine genes for B chains (four are shown in the figure). The principal expressed heterodimers for HLA-DR are AB1, AB3, AB4, and AB5. In the region between HLA-DP and HLA-DQ lie the closely linked TAP1, TAP2, LMP2, and LMP7 genes. The TAP genes encode peptide transporters, whereas the LMP genes encode proteosomes that fragment proteins into peptides. This cytoplasmic system is believed to be responsible for production and delivery of peptides to MHC class I molecules before their movement to the cell surface.

Structure and Antigens of the Major Histocompatibility Complex

There are two structural types of MHC molecules, called class I and class II. The molecules of both classes are active in antigen recognition and help focus immune defenses during invasions from the microbial world. They are also engaged in the communication that occurs between cells during the immune response. MHC molecules act by binding peptide fragments of antigens that have been processed in specialized antigen-presenting cells. Clonally determined antigen receptors on T cells then recognize and bind to specific peptide-MHC complexes, setting into motion the appropriate immune response. Segments of MHC molecules show sequence homologies with immunoglobulins, T cell antigen receptors, and T cell interaction molecules such as CD4 and CD8, which suggests that all these molecules share a common evolutionary ancestry.

The sequence and structure of MHC molecules have been extensively elucidated, and it has been determined that the polymorphic, or antigenic, portions of MHC molecules are quite small. In fact, the polymorphic portions frequently comprise only one to four amino acid substitutions encoded in regions of DNA nucleotide sequence hypervariability. A specific configuration in an MHC molecule resulting from particular substitutions of amino acids is called an epitope.


MHC class I antigens consist of two polypeptide chains held together noncovalently. One chain is heavy (44 kd) and glycosylated, and it determines antigen specificity. The extracellular portion of this class I heavy chain is divided into three domains, designated α1, α2, and α3. The other chain is a small (11.5 kd) protein known as β2-microglobulin [see Figure 2]. Class I heavy chains are the gene products of three MHC loci, designated HLA-A, HLA-B, and HLA-C [see Table 1]. There are many alleles for each locus; therefore, considerable polymorphism exists. β2-Microglobulin is encoded by a gene on chromosome 15. Both the β2-microglobulin and the α3 domain of the heavy glycosylated chain of MHC class I antigens demonstrate considerable structural similarity to the constant region of the heavy chain of IgG (CH3).


Figure 2. MHC Molecules

MHC molecules are of two structural types with very similar peptide-binding sites on the membrane-distal surface. (a) MHC class I molecules consist of heavy chains made up of three polypeptide domains (α1, α2, α3) and a noncovalently associated light chain, β2-microglobulin. (b) MHC class II molecules are heterodimers of α and β chains with a very similar overall structure and peptide-binding surface.20

Table 1 Antigens of the HLA System



Number of Antigenic Specificities*

Number of DNA Variants

Class I




Class II

HLA-DR (1–18)
HLA-DR (51–53)


24 (cellular)

6 (cellular)

25 (DQA1)
56 (DPB1)
20 (DPA1)
106 (DPB1)

*Antigenic specificities are defined by reactivity with HLA-specific sera from multiparous women (serologic specificity) or by proliferative response of cells (cellular specificity).
Variants at each locus; most variants result in a different expressed amino acid sequence.

MHC class I molecules have been crystallized, and their structure has been determined by x-ray diffraction to a resolution of 3.5 angstroms (Å).1 Two of the heavy-chain domains, α1 and α2, are located at the membrane-distal portion of the heavy chain and form a groove along the top surface of the molecule. The sides of the groove are composed of α helices from the α1 and α2 domains, and the base is composed of eight antiparallel β-pleated sheets from these domains. The hypervariable (antigenic) regions are found mostly along the sides of the groove, but there is also variability in the β-pleated sheet region. The rest of the molecule shows minimal variability in relation to other molecules of the same HLA locus. In the crystals studied, the groove, which faces away from the cell membrane and is approximately 25 Å long and 10 Å wide, contains material representing processed antigen (i.e., peptide fragments). When peptides eluted from purified class I molecules are sequenced, they show patterns of amino acids, called motifs, that bind to particular sets of HLA class I molecules.2 These findings helped confirm the hypothesis that MHC molecules bind and present processed antigens to responding T cells and that the T cell receptor (TCR) recognizes foreign antigen as a peptide in the context of self-antigen; that is, it binds to a surface composed of both MHC and a bound peptide.

MHC class I antigens can be expressed on all cell types except erythrocytes and trophoblasts and can be detected by staining with labeled antibodies. Striated muscle cells and liver parenchymal cells are normally negative for class I antigens (i.e., they lack class I molecules or express only a low density of class I molecules), but in inflammatory states, these cells may become strongly positive for class I antigens.


Some antibodies, elicited by immunizations with histoincompatible cells, react with a limited variety of cells, most notably B cells, monocytes, dendritic cells, and activated T cells. Normally, these cells are the only ones found to bear MHC class II antigens. As is the case with class I antigens, however, inflammatory states cause many tissues to express class II antigens.

Each MHC class II antigen consists of two membrane-inserted glycosylated polypeptides, designated α (34 kd) and β (28 kd), which are bound together noncovalently [see Figure 2]. The extracellular portion of the α chain is divided into two domains, designated α1 and α2; the extracellular portion of the β chain is also divided into two domains, β1 and β2. Class II antigens are encoded by the HLA-D region, which is divided into at least three subregions: HLA-DP, HLA-DQ, and HLA-DR [see Figure 1].

Crystallographic studies indicate that MHC class II molecules have a structure similar to that of MHC class I molecules, with the α1 and β1domains forming a groove in which β-pleated sheets form the base and α helices form the sides.3 As in MHC class I molecules, the hypervariable (antigenic) regions of MHC class II molecules are located primarily along the groove, which again indicates a molecular basis for TCR recognition of foreign antigen together with self-MHC.

Class II MHC antigens can be identified by the use of sera from multiparous women that react predominantly with B cells. A serum is first exposed to platelets from a pool of many persons, because platelets contain MHC class I, but not MHC class II, antigens and thus will absorb antibodies to class I antigens, leaving antibodies to class II antigens in the serum. The naming of genes from the HLA-D region is now based on knowledge of the biochemistry of expressed antigens and on a growing database of DNA nucleotide sequences. The gene encoding theHLA-DR α chain, for example, is called DRA. Similarly, the closely linked genes encoding the β chains have been named DRB1 (encoding the β chains for DR1 through DR18), DRB3 (encoding the β chain for DR52), DRB4 (encoding the β chain for DR53), and DRB5 (encoding the β chain for DR51). Because DRB2 expresses no protein product, it is called a pseudogene. Each of the HLA-DR β chains associates with the common nonpolymorphic HLA-DRA α chain to form functional class II HLA-DR molecules. HLA-DRA α chains are always the same; the difference in HLA-DR antigenic alleles is accounted for by variations in the genes encoding the HLA-DR β chains. The HLA-DQ locus contains the genes DQA1, DQB1, DQA2, and DQB2. DQA2 and DQB2 are pseudogenes, whereas the products of DQA1 and DQB1—that is, the α and β chains of HLA-DQ—are both polymorphic. HLA-DP gene organization is similar to that of HLA-DQ [see Figure 1].


The nomenclature of the HLA system is coordinated through the World Health Organization Nomenclature Committee for Factors of the HLA System.4 The prefix for the gene name is HLA, followed by a hyphen, then a locus name (e.g., DRB1, DQA2, C). A specific allele (DNA sequence variant at a locus) is denoted by appending an asterisk to the gene name followed by a unique alphanumeric identifier for that allele. The alphanumeric identifier is composed of up to nine characters: AACCSSXXN, where AA is an integer that refers (when possible) to the serologic family of which the allele is a member; CC is an integer defining the nucleotide coding variant resulting in a unique peptide product; SS is an integer defining synonymous variants (different DNA sequence but same amino acid sequence) of a coding variant; XX is an integer defining variants outside the coding region. An N is appended to the identifier if the allele is a null or nonexpressed variant. Thus, HLA-DRB1*030502 encodes a DR molecule that is serologically in the DR3 group and has a different amino acid sequence fromDRB1*0301, DRB1*0302, DRB1*0303, or DRB1*0304. It also has a different nucleotide sequence from DRB1*030501, but has the same amino acid sequence, making it a synonymous variant.


Two terms, haplotype and linkage disequilibrium, describe important associations between MHC genes. Haplotype refers to the set of closely linked genes on any one chromosome. Every person has two haplotypes of the MHC, one from each parent. Each haplotype has a particular set of antigens determined by the HLA-A, HLA-B, HLA-C, HLA-DR, and other loci.

The second term, linkage disequilibrium, refers to the observation that in a population, some HLA antigens coincide within a single haplotype much more frequently than expected. If discrete genes were distributed independently throughout the population, the frequency at which any two linked antigens encoded at different loci would occur within a haplotype is the product of their frequencies in the population. However, in whites, the HLA-A1 antigen and the HLA-B8 antigen are associated six to 21 times more often than would be predicted from their gene frequencies. Such linkage disequilibrium may occur because not enough evolutionary time has elapsed for the genes governing the antigens to be evenly distributed or because such an association results in a selective advantage to the individual. Recombination, or crossover, takes place during meiosis and occurs about 1.5% of the time between MHC class I and MHC class II loci. Over many generations, recombination leads to an equilibrium of linked alleles in a population unless selective pressures favor survival of certain haplotypes. A hypothetical example of such selection would be the survival of persons bearing HLA haplotypes that confer resistance to epidemics, such as smallpox and plague. Racial differences are reflected in marked variations in the frequencies of certain HLA antigens and haplotypes. Fewer, though often striking, examples of such differences are also observed in various ethnic groups.5

Role of MHC in Immune Response


When lymphocytes from one person are cultured with those from another, the cells are stimulated to divide. This division, which can be measured from the rate of uptake of 3H-thymidine into the cells, is called the mixed lymphocyte reaction (MLR). By preventing the division of one of the sets of cells by treatment with mitomycin or irradiation, it is possible to study the antigens on the membrane of the treated cells that stimulate this proliferative response. In humans, HLA-DR antigenic determinants are mainly responsible for evoking a primary MLR. HLA-DQ antigens play a lesser role, and HLA-DP antigens do not appear to be involved in the primary MLR. However, responding lymphocytes that have been primed by previous exposure to HLA-DQ or HLA-DP antigens proliferate vigorously when reexposed to the same antigen in a secondary MLR. The primary MLR is driven by the very high precursor frequency of naive cells having affinity to HLA-DRB1, not by primed memory cells.


The breakdown of protein molecules into peptide fragments is an important part of the process by which antigens are presented to T cells and other immune effector cells. MHC molecules come to the cell surface with peptides already bound. Proteins are first degraded internally, and the peptide fragments are bound to MHC class I and MHC class II molecules within the cell. Class I molecules are expressed on virtually all tissues. Virally infected cells are recognized principally by class I-restricted T cells, usually those with a cytotoxic function. In contrast, class II-directed T cells are restricted to antigen-presenting cells of the immune system (i.e., B cells, macrophages, dendritic cells, or Langerhans cells) that are principally concerned with defense against external infectious agents. Because class II-positive cells also carry class I molecules, they may act as antigen-presenting cells for both exogenous and endogenous proteins [see 6:IV Cell-Cell Interactions, Cytokines, and Chemokines in Immune Response Mechanisms].

Exogenous and endogenous antigens reach the cell surface by different pathways. Exogenous proteins are taken up into endosomes or lysosomes, where they are catabolized. Peptides from exogenous proteins are generally bound to MHC class II molecules, and the class II-peptide complexes are then brought to the surface for presentation to T cells. Peptides from endogenous proteins (e.g., secretory proteins or products of viral infection) appear to be complexed in the endoplasmic reticulum to MHC class I molecules. Genes called LMP, which are also located in the MHC region, encode proteins that are responsible for breaking down proteins into small peptides (eight to 10 amino acids long); closely linked TAP genes encode chaperones that transport peptides across intracellular membranes [see Figure 1].6,7,8 This system delivers peptides of intracytoplasmic origin to newly formed class I molecules. As noted, certain peptide sequence motifs are known to be characteristic of peptides eluted from purified molecules of a given MHC allele.9,10 These findings indicate that the allelic sequence differences at the margins of the peptide-binding groove determine which peptide sequences will bind. Class I-bound peptides are usually nine amino acids long, with residues at particular locations that have similar charge or hydrophobicity (e.g., at positions 1, 3, and 9) for different groups of HLA alleles. In addition, a number of synthetic peptides representing immunogenic portions of infectious agents or other foreign proteins align on similar common motifs. Peptides eluted from purified HLA-DR class II molecules are variable in length, up to 25 residues, and have a minimal length of 13 to 14 amino acids. The motifs for DR1 represent a positively charged residue at position 1, a hydrogen bond donor at position 6, and hydrophobic residue at position 10.11 Prediction of binding affinity for a given HLA sequence is becoming common practice for development of peptide vaccines and studies of the specific immune response to protein antigens.10,12


The corecognition of MHC and peptide fragments of an antigen bound in the groove of the class I or class II molecules appears to require that the binding surface of the TCR and the binding surface formed by MHC plus peptide be attached at multiple points [see 6:III Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors]. Each T cell clone is specific for a self-MHC-peptide complex and generally does not have sufficient affinity for MHC or peptide to bind well to either component alone. There is extensive evidence that the development of the T cell repertoire in the thymus begins during the fetal period and continues well into adult life as new precursor cells from the bone marrow mature in the thymus. In this process, many potential clones are destroyed and others are selected to mature. The selected T cell clones then leave to populate the rest of the body. The MHC of the host plays the major role in selection: T cell clones that are strongly autoreactive to self-MHC molecules are eliminated, leaving clones with weak affinity to self-MHC to survive. Because the surviving clones have a large variety of T cell receptor rearrangements [see 6:III Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors], the individual retains the necessary repertoire of T cell clones that can recognize self-MHC plus peptide. The successful crystallization of a complex consisting of a human TCR, its viral peptide, and the HLA-A2 molecule that binds it has revealed the configuration and extent of the binding surface between the TCR and the MHC-peptide surface. The axis of the TCR is diagonal to that of the MHC helices, so that it covers a large portion of both α helices and the peptide between them. Although the extensive MHC polymorphisms increase the likelihood that a particular peptide fragment will be bound so that it can be recognized by T cells, a given individual has a small repertoire of such MHC binding sites compared with the rich combinatorial possibilities in the TCR gene complex. The inheritance of multipleHLA loci from two parents, however, increases the potential for recognizing a greater number of different self-MHC-peptide complexes and therefore increases the likelihood that at least some persons will survive a given infection.

The alloresponse, which is the immune response mounted against another individual's cells, is a special case. Except for direct activation of T cell subsets with bacterial superantigens (e.g., staphylococcal exotoxins), the in vitro proliferation of T cells in the MLR is the most vigorous antigen-specific response known because it does not require the priming that is needed to induce proliferation to microbial antigens. Transplantation is, of course, a technological artifact and would not have been encountered during evolution; only pregnancy has the potential for exposing the cells of one person to those of another having different HLA haplotypes. The allobarrier could have made pregnancy difficult or impossible except for the presence of several imperfectly defined mechanisms at the placental level that protect the fetus from rejection. The existence of such mechanisms suggests that the need for MHC polymorphisms is most important and requires special protection at the maternal-fetal interface.

Alloreactive T cells are known to either indirectly perceive allo-MHC peptides presented on self-MHC molecules or directly recognize intact allo-MHC molecules that hold a self-peptide.13 Because a number of peptides derived from endogenous proteins occupy MHC binding sites at all times, such self-peptides need not be polymorphic or unique to an individual. The functional significance of the indirect, as well as the direct, pathways in transplantation has been established. It has been shown in animal models that immunization with synthetic allopeptides alone can cause accelerated graft rejection,14,15 whereas administration of such peptides by the oral or intrathymic route can increase tolerance for alloantigens. Also, priming to allopeptides presented by self-MHC molecules is a feature of rejection activity in human transplant recipients.16


The MLR leading to the generation of cytotoxic T cells requires two distinct types of responding T cells. The process begins with the stimulating cell—a B cell, dendritic cell, or monocyte—which has both MHC class I and MHC class II molecules on its surface. The class II molecule stimulates subsets of responding T cells to proliferate and become helper T cells. This subset is marked by the CD4 antigen. The class I molecule sensitizes a second subset of T cells, which become cytotoxic T cells if stimulated by the proliferating helper T cells. One of these stimulatory signals is mediated by the lymphokine interleukin-2 (IL-2). This second T cell subset is marked by the CD8 antigen. Cytotoxic T cells that develop against cells that differ only in their class II antigens bear the CD4 marker. The two stimuli—the one that induces helper T cell proliferation and the one that sensitizes T cells to become cytotoxic—can be delivered by different cells [see Table 2]. This type of cell interaction and cooperation is thought to mirror in vivo events that lead to graft rejection by cytotoxic T cells, showing why it is desirable to have both class I antigen and class II antigen compatibility between donor and recipient cells.


Table 2 Cell-Mediated Lympholysis in a Mixed Culture

It was formerly thought that CD4+ T cells were simply helper lymphocytes and that CD8+ T cells were either cytotoxic or suppressor lymphocytes, but these functional divisions do not appear to be clear-cut. Ongoing molecular studies indicate that the CD4 surface molecule is closely associated with the TCR and guides interaction between T cells and antigen-presenting cells by binding to a nonpolymorphic region of MHC class II molecules [see 6:III Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors]. Similarly, the CD8 molecule binds to MHC class I molecules on antigen-presenting cells. CD4 and CD8 molecules also increase the strength with which the TCR complex binds to the antigen-MHC complex. In addition, these surface molecules participate in signaling activation of the adherent T cell.

Immune Response Genes

As previously mentioned, many lines of evidence indicate that MHC class II molecules are the expressed products of immune response (Ir) genes; in other words, immune responsiveness can be a direct function of antigen presentation. If an antigen fragment is not bound to a class II molecule, a person's immune system is unable to recognize it. Certain diseases in animals—including virally induced forms of leukemia, mammary tumors, and lymphocytic choriomeningitis—have been linked to polymorphism of MHC class II genes. However, the ability of specific HLA antigens to confer susceptibility to clinically important infectious agents has rarely been suggested (see below). It is likely that evolution has resulted in selection of MHC alleles that are capable of binding at least some portions of antigenic molecules on infectious agents. In addition, the duplication of class II genes with expression of HLA-DR, HLA-DQ, and HLA-DP sets of molecules increases the likelihood that a response can be initiated in a given case. In particular, polymorphisms on both α and β chains of HLA-DQ and HLA-DP provide considerable variation in binding configurations, especially when αβ dimers are composed of chains inherited from both parents; for example, αmotherfather may provide a peptide-binding molecule not present in either parent. There are also many non-MHC influences on immune responsiveness; none of these have yet been well characterized clinically.

Studies in humans have also suggested the ability of the MHC to suppress immunologic responses to environmental agents, such as streptococcal infection, schistosomiasis, and leprosy, as well as antigens from cedar pollen and hepatitis B vaccine. For example, the in vitro IgE response to cedar pollen antigen is suppressed by T cells of persons bearing HLA-DQ3, but the mechanisms of such T cell-mediated suppression are ill defined.17,18


Several complement proteins are encoded by genes that are linked to the MHC. These proteins include C2 and factor B (Bf), which are closely linked and also similar in structure, suggesting gene duplication. In addition, two loci for C4 (C4A and C4B) are closely linked to C2 and Bf. The C2 deficiency associated with systemic lupus erythematosus is associated with the HLA-A25, B18 haplotype. Indeed, researchers have found extended haplotypes in which the same HLA-B, HLA-DR, HLA-DQ, and complement types are found in apparently unrelated persons with the same disease. These circumstances could result from a mutation occurring in a common ancestor. Alternatively, there may be selective pressures to keep in close proximity genes that produce proteins that act together.


MHC genes are possibly also important in a variety of nonimmunologic cell-cell interactions. In 1976, a study showed that when a male mouse was presented with two females in estrus that were genetically identical except in portions of the MHC, the male would most often choose to mate with the female of an MHC type different from his own.19 Further experiments showed that the male discriminated between MHC types by sense of smell. The advantage most apparent in this example of opposites attracting is that the heterozygosity of genes in the region that encodes for MHC ensures a wider range of immune defenses for the hybrid progeny of such matings. There is no evidence that humans can sense HLA antigens, however.

Disease and the Major Histocompatibility Complex


Many diseases have been associated with certain MHC antigens [see Table 3]. Such associations per se show only that the MHC molecules or some other genes closely linked in the HLA region have an influence on initiation or expression of disease. A relative risk of 5, for example, means only that there is a fivefold increase in the likelihood of disease in a person with a particular HLA antigen, compared with someone who does not have that antigen. It indicates nothing about the frequency of the disease itself, which may be rare or common. One explanation for such associations is that the disease in question is related to a deficiency in the immune response to a particular causative organism. There is increasing evidence, however, that organ-specific HLA-associated diseases—such as type 1 diabetes mellitus, multiple sclerosis, Graves disease, the glomerulonephritides, celiac disease, ankylosing spondylitis, and rheumatoid arthritis—have a major component of autoimmunity.

Table 3 Diseases Showing Positive HLA Antigen Association(s)22



Serologic HLA Antigen

Relative Risk*


Ankylosing spondylitis
Reiter syndrome
Acute anterior uveitis
Reactive arthritis
Psoriatic arthritis

Juvenile rheumatoid arthritis
Juvenile rheumatoid arthritis (pauciarticular)
Rheumatoid arthritis
Sjögren syndrome
Systemic lupus erythematosus






Gluten-sensitive enteropathy
Chronic active hepatitis
Ulcerative colitis
IgA deficiency




Idiopathic hemochromatosis

Pernicious anemia
Hodgkin disease

A3, B14



Dermatitis herpetiformis
Psoriasis vulgaris
Psoriasis vulgaris (Japanese)
Pemphigus vulgaris (Jewish)

Behçet disease (white)
Behçet disease (Japanese)




Diabetes mellitus, type 1

Graves disease

Graves disease (Japanese)

Addison disease
Subacute thyroiditis
Hashimoto thyroiditis
Congenital adrenal hyperplasia




Myasthenia gravis
Multiple sclerosis

DR2, DQ6



Bipolar disorder




Idiopathic membranous nephropathy
Goodpasture syndrome
Minimal change disease
IgA nephropathy (French, Japanese)
Gold/penicillamine nephropathy
Polycystic kidney disease




Tuberculoid leprosy (Asians)
Paralytic polio
Low versus high response vaccinia
Falciparum malaria, severe




In animal models in which appropriate breeding studies have been done, it has been demonstrated that autoimmune states depend on five to 15 randomly segregating genes, one of which is in the MHC. Polygenic etiology of human autoimmunity is very likely, and the HLA components may be useful targets for intervention, particularly in diseases in which HLA presentation of an immunogenic self-peptide is a key event. Also, with the development of inflammation, de novo expression of HLA class II molecules on tissue cells may provide the immune stimulus for perpetuation of the autoimmune process. For example, patients with thyroiditis show aberrant expression of HLA-DR on thyroid cells, providing a possible mechanism by which thyroid antigen could be presented to T cells.

There has been some progress in discerning which diseases may be directly related to immunogenic peptide presentation. Analysis of the sequences of genes encoding MHC class II molecules from patients with type 1 diabetes mellitus suggests that inheritance of particular HLA alleles is important in determining susceptibility to this disease, involving a T cell-mediated autoimmune response to pancreatic islet cell antigens. Resistance to type 1 diabetes mellitus is strongly associated with the presence of aspartate at position 57 of the HLA-DQB chain. In persons with the HLA-DR2 haplotype, for example, the relative risk for the disease drops to 0.2 [see Table 3]. HLA-DR2 is in linkage disequilibrium with HLA-DQB alleles, such as DQB1*0602, encoding aspartate at position 57. In contrast, when aspartate is not present at position 57, particularly in persons with the HLA-DR3 or HLA-DR4 haplotype, there is an increased risk of type 1 diabetes mellitus. Amino acid residue 57 on the HLA-DQB chain would lie toward one end of the groove; aspartate at that position may influence binding of a peptide to this class II molecule, causing reduction of helper T cell responses or activation of suppressor T cell responses to pancreatic islet cell antigens. Many studies in certain ethnic groups have shown that the greatest susceptibility to type 1 diabetes mellitus is related to HLA-DQ. The DQA/DQB heterodimer DQA1*0301/DQB1*0201 is associated with the highest risk. What is of interest here is that this heterodimer is uncommon, occurring mostly in persons who have inherited the DQA gene from one parent and the DQB from the other. WhereasDQA1*0301 and DQB1*0201, usually found with DR4 and DR3 haplotypes, respectively, separately increase the risk for type 1 diabetes mellitus, together they provide the highest risk of disease. As noted previously, the formation of a heterodimer from the products of genes inherited from both parents does occur with the HLA-DQ molecule. The hypothesis is that this “new” peptide-binding site will be most effective in the presentation of pancreatic islet cell autoantigen. Definition of the binding motifs of this site may provide a clue to the antigen. There are additional and independent effects of HLA-DR—particularly the DR4 alleles, some of which are associated with enhancement and others with suppression of the risk for diabetes. Amino acid differences in the hypervariable regions of MHC class II molecules have also been associated with such auto immune disorders as pemphigus vulgaris and rheumatoid arthritis.

The association of narcolepsy with HLA-DR2 (DRB1*1501) is more than 90%, but the highest association is with HLA-DQA1*0102/DQB1*0602. The HLA effect is dominant, not recessive, and there is no indication of an immunologic defect in affected persons. An abnormality in a peptide neurotransmitter or its receptor has been postulated, but the relation to the HLA-D-region genes remains elusive.

About 80% to 90% of celiac disease is associated with HLA-DQA1*0501/DQB1*0201. The peptide-binding groove of this molecule is known to bind a peptide of wheat protein gliadin, which is a potentiating if not etiologic factor in this disease.

Although an HLA molecule may determine specificity to a particular autoantigen, it is possible that genes controlling other factors (e.g., the production of antigen receptors, specific subsets of regulatory cells, or helper and suppressor molecules) are responsible for a general tendency toward an abnormal immune response. Additional study of the peculiar role of the HLA system in autoimmunity may well reveal mechanisms of autoimmune disease that are currently unknown.


Figure 1 Laura Brown.

Figure 2 Seward Hung.


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Editors: Dale, David C.; Federman, Daniel D.