Autoimmune Disease and the Major Histocompatibility Complex: Therapeutic Implications THOMASA.DALTON,M.D.,J.CLAUDEBENNETT,M.D.,

Birmingham,A/abama

A hereditary basis for the predisposition to several autoimmune diseases has long been suspected. A relationship between diseases and genes that encode various immune effector proteins is now recognized. Many of these genes are components of the major histocompatibility complex (MHC). Recent studies have provided insights into the mechanism by which MHC antigens can influence the tendency to the expression of autoimmune disease. These fmdings have also provided the rationale for designing specific imnumotherapeutic interventions.

he ability to discriminate between self- and non-self antigens is an essential feature of the normal immune system. Autoimmunity is a state in which the recognition processes are altered and the self is subjected to attack by the immune response. Hereditary factors have long been suspected in the predisposition to a variety of autoimmune diseases, and this is supported by familial clustering of these disorders as well as concordance studies in monozygotic twins. Associations between diseases and genes that encode various immune effector proteins are now recognized. Many of these genes are components of the major histocompatibility complex (MHC). The presence of MHC molecules is required for the processing and presentation of both foreign and self-antigens to the immune system. Recent breakthroughs in our understanding of the intricacies of antigen presentation have provided insights into the mechanism by which MHC antigens can influence predilection to the expression of autoimmune disease. These discoveries have also provided the rationale for novel interventional strategies aimed at specific molecular sites involved in the immune response.

T

THE MHC STRUCTURE

From the Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama. Requests for reprints should be addressed to Thomas A. Dalton, M.D., Division of Gastrdenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37205. Manuscript submitted June 1. 1991, and accepted in revised form August 9, 1991.

The MHC includes the genes for the human leukocyte antigens (HLAs). These genes as well as those that encode many other components of the immune system are clustered on the short arm of chromosome 6 and represent approximately 1/3,00Oth of the total human genome and several hundred individual genes. The MHC is a polymorphic gene complex, meaning that multiple alleles exist for each genetic locus. The MHC is subdivided into class I (HLA-A,-B, and -C), class II (HLA-DR, -DQ, and -DP), and class III (genes for certain complement components). The class I and II proteins are transmembrane cell surface glycoproteins and are required for the highly integrated molecular interactions involved in recognition of both self- and foreign antigens by T lymphocytes. The HLA class I glycoprotein is present on all nucleated cells and platelets. It consists of a “heavy” chain subunit anchored to the cell by a

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a, Domain

a2Domain 82

Microglobulin

a3 Domain

Figure 1. Schematic representation of the MHC class I molecule. The heavy chain, with transmembrane anchor segment, is noncovalently associated with &-microglobulin. NH2 = amino terminus; COOH = carboxy terminus; S = disulfide bond; CQ, 012, and cq are the three extracellular domains.

transmembrane hydrophobic “tail” and an extracellular hydrophilic region with three domains ((~1, LYE,(~3).The heavy chain is noncovalently associated with the smaller µglobulin, a nonpolymorphic protein encoded outside the MHC (Figure 1). The czi and as domains are polymorphic and display structural determinants specific to the individual. Exciting crystallographic studies from the laboratory of Don Wiley have provided the structure for this class I molecule [1,2]. Consistent with the presence of hypervariable amino acid sequences in 011and 012, it appears that these domains comprise the “business end” of the molecule. These structures appear to create a groove that serves as a binding site for appropriately processed antigen (Figure 2). The class II HLAs have a more limited distribution and are found on B lymphocytes, macrophages, monocytes, dendritic cells (epithelium), and activated T lymphocytes. In a manner analogous to the class I molecules, these transmembrane glycoproteins are composed of (Yand 0 subunits. The (~1and pi domains determine the molecule’s variable region and form the peptide-binding groove [3-51.

The HLA molecules are critical for the recognition of antigen by a T lymphocyte by way of its highly specific receptor (TCR). Class I MHC molecules are restricted to interaction with receptors on CD8+ (cytotoxic) lymphocytes, which generally are involved in recognition and attack on virus-infected cells and foreign tissue grafts. Upon exposure to the foreign antigen-HLA complex, the T lymphocyte

Figure 2. The crystallographic structure of the MHC class I molecule. fl-pleated regions are shown as thick arrows in the amino to carboxy direction and a-helices are depicted as helical ribbons. Disulfide bonds are shown as two connected circles. Top. The four domains of the molecule. The asterisk indicates the antigen-binding groove. psm = µglobulin; N = amino terminus; C = carboxy terminus. Bottom. Top view showing the antigen-binding groove. P-pleated sheets form the floor, which is flanked by oc-heiices of the (~1 and (~2 domains. N = amino terminus. (Reprinted by permission from [l]. Copyright 1987 Macmillan Magazine Limited.)

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differentiates into a mature cytotoxic cell (CTL), which is now restricted to interaction with that specific antigen in combination with its presenting class I molecule (Figure 3, top). The class II molecules are restricted to interaction with CD4+ T lymphocytes. Foreign antigens, in conjunction with specific class II molecules, are presented to CD4+ T cells by antigen-presenting cells (APCs), resulting in the induction of T-cell proliferation, lymphokine production, and subsequent synthesis of immunoglobulin by B lymphocytes (Figure 3, bottom). The APC is usually. a macrophage or monocyte but others include the Langerhans cell in the skin, dendritic cells of the lymph nodes and spleen, and the interdigitating follicular cells of the thymus. Two models of antigen presentation have been described: (1) an endogenous pathway utilized by the class I system, and (2) an exogenous pathway utilized by the class II molecules. The endogenous pathway is the mechanism by which processed antigen derived from intracellular microbes (e.g., viruses) is complexed with class I precursor, presumably in the Golgi apparatus, and then presented to the cell surface for recognition and attack by CDS+ CTLs. In contrast, extracellular antigens are taken into endosomes where they are processed for binding to class II molecules and subsequent presentation to CD4+ T lymphocytes. The strict dichotomy between these pathways has been questioned recently and evidence exists that class II molecules can also utilize the endogenous pathway of antigen presentation [6,7]. It is well known that antigen presentation does not require the participation of the intact antigenic protein and that only a small peptide segment is sufficient to initiate an immune response. This process requires the interaction of three essential components: the MHC molecule, peptide antigen, and TCR that is both specific for and restricted to the relevant antigen-MHC complex [8]. T cells are committed early in development to the HLA-antigen complex with which they will interact (see below). The CD3 molecule is a transmembrane protein associated with both MHC I and II and is responsible for signal transduction.

THE MHC AND DISEASESUSCEPilBlLlTY Associations between certain HLAs and disease have been demonstrated from population studies (Table I) [7,9,10]. Unfortunately, causality cannot be derived from such studies and it is clear that the simple presence of an HLA is insufficient to infer pathogenesis of disease. This is evidenced by the fact that most persons carrying a given HLA type

DISEASE AND MHC / DALTON

T-CeJ

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Proliferation

Figure 3. T-cell response to antigen presentation. Top. In the presence of MHC class l-antigen complex, CD8+ T lymphocytes are stimulated to proliferate and differentiate into restricted cytotoxic T cells (CTL). The CD3+ protein is required for signal transduction. TCR = T-cell receptor; Ag = antigen. Bottom. In the presence of MHC class II-antigen complex, CD4+ T lymphocytes release lymphokines that induce restricted T-cell proliferation or B-lymphocyte activation and differentiation. T = T lymphocyte; B = B lymphocyte; P = plasma cell; APC = antigen-presenting cell.

will not develop the associated disease and that the disease does occur in persons who lack that marker. Therefore, it seems that disease-associated MHC molecules play a permissive rather than a causative role in diseases. In the normal immune system, T cells are able to discriminate between self- and foreign ligands. The system is activated by recognition of the MHC foreign antigen but does not respond to MHC selfantigen. This phenomenon of immunologic tolerance is initiated during early thymic development. Potentially autoaggressive T cells are either clonally deleted (negative selection) or rendered refractory to subsequent stimulation by the antigen (anergy) [11,12]. This latter concept of T-cell anergy allows for a reservoir of cells potentially capable of autoimmune behavior. T-cell-dependent autoimmunity results when self-tolerance is compromised. It has been suggested that cross-reactive viral or bacterial antigens might be capable of stimulating these normally self-tolerant lymphocytes [13].

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Fundamental to an understanding of T-cell activation is the nature of MHC-peptide-TCR interactions. This is evidenced by the observations that the interactions between peptide and class II molecules will accept 80% to 90% of single amino acid substitu-

tions in the peptide without significant effect. However, the TCR will tolerate only 10% to 20% single amino acid substitutions and still recognize the peptide-MHC complex [14,15]. A preponderance of definite or suspected human autoimmune diseases is associated with specific class II HLA haplotypes. Notable exceptions include the HLA class I-associated human spondyloarthropathies (Table I). The extensive polymorphisms exhibited by class II molecules are derived from three or four discrete hypervariable regions in the ,& domain [16]. Approximately 80% to 90% of patients with seropositive rheumatoid arthritis (RA) carry either HLA-DRl or one of three HLA-DR4 variant (Dw4, Dw14, Dw15) haplotypes. All of these haplotypes share very similar amino acid sequences (epitopes) in the third hypervariable region (HVR) on the DR& domain at positions 65-74 1131. According to the model of Brown et al [5], the third HVR would localize to one side of the MHC bonding site and is characterized as a distinct epitope capable of stimulating T-cell recognition [17]. While cross-sectional prevalence and twin concordance studies strongly indicate the contributions of environmental and other nongenetic influences in the pathogenesis of RA, the demonstration of shared epitopes among the different HLA class II alleles associated with the disease provides strong support for an MHCassociated genetic predisposition. The concept of shared epitopes is further evidenced in a recent study of RA in the Yakima Indians [18]. This North American Indian tribe has been shown to have a very high prevalence of severe seropositive RA. The HLA-DR4 and -DRl haplotypes commonly associated with RA are uncommon in this population. Instead, a rare HLA-Dwl6 marker was identified in 83% of Yakima individuals with RA and 60% of Yakima control subjects. It appears to be an allele of the DR/3l locus, and comparison of the amino acid sequences in the 67-74 positions (third HVR) shows that they are identical to the homologous DRl and DR4 sequences that confer increased susceptibility to RA. These observations provide very convincing evidence for an identifiable genetic contribution to this autoimmune disease. A similar analysis of juvenile-onset insulin-dependent diabetes mellitus (IDDM) has revealed haplotypes with increased (HLA-DR4, -DR3, and -DRl) and decreased (HLA-DR2, -DR5) susceptibility. However, the more significant association appears to localize to codon 57 in the HLAD&p chain [19]. These data are supported by the non-obese diabetic mouse model that expresses a

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TABLE I AssociationBetween HLA and Autoimmune Diseasein Whites* Disease

Antigen

Pa;;yts OO

Co;t$ls o

ReMv

Ankylosing spondylitis

627

90

9.4

87.4

Reiter’s syndrome

B27

79

9.4

37.0

Rheumatoid arthritis (RA)

DR4

56

25

4.0

Sjiigren’s syndrome

DR3

78

26.3

9.7

Sjogren’s syndrome with RA

DR4

64

27

4.7

SypL$

Ef$

ii

28.2

5.8 s::

lupus erythematosus

DQwl

76

25 55

Subacute cutaneous LE

DR3

77

22

10.8

Hydralazine-induced

DR4

73

32.7

2.7

Dermatomyositis

DR3

74.4

42.2

3.9

Scleroderma

DR5

53

la.3

5.0

CREST syndrome

DR3

57.1

17.7

6.0

Behcet’s disease

B5

41

10.1

6.3

Juvenile rheumatoid arthritis (pauciarticular)

DR5

50

16.2

5.2

Giant cell arteritis

DR4

39.6

19.2

a.2

Psoriasis vulgaris

Cw6

a7

33.1

13.3

Psoriatic peripheral arthritis

838

23

4.0

7.3

Psoriatic spondylitis

827

57

a

20.8

16 ;8Rw3

i;

17

3.4 3.0

Addison’s disease

Dw3

70

21

a.8

Graves’ disease

B8 Bw35 Dw3

44 ::

2.5 5.0 5.5

LE

Myasthenia gravis

Multiple sclerosis

z

la

E 2

B8 Dw3

ii;

1’2;

73.0

Hemochromatosis

A3

71

20

9.0

Chronic active hepatitis

B8 DRw3

YE

16 7

9.2 4.6

Celiac disease

21

1.8

A3 B7 Bw2 DRw2

2 22

2.0 1.9

3.8 8.6

,dapted from [9, 101 and Schwartz BD. The major histocompatibility complex and diseas sceptibility. In: Wyngaarden JC, Smith H, editors. Cecil’s textbook of medicine. 18th ec liladelphia: WB Saunders, 1988: 1966-8.

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change at position 57 of the homologous class II p chain [20]. Another very clear example of genetic susceptibility in autoimmunity is pemphigus vulgaris (PV), in which autoantibodies are directed against an epidermal cell surface protein. The patients have chronic blistering and recurrent infections. Here a change in codon 57 of the D&/3 chain, again implicating HVR, can confer nearly absolute susceptibility to the disease given the presence of the appropriate class II haplotype [21,22]. It is apparent that codon 57 on the D&p1 chain occupies a critically important site in the MHC-binding groove and has a major influence on antigenic binding and TCR interactions with the antigen in both IDDM and PV. Individuals with myasthenia gravis (MG) have autoantibodies directed against the nicotinic acetylcholine receptor (AchR) and increased frequencies of the HLA-B8, -DR5, -DR3, and -DQw2 MHC antigens. In the case of MG, not only is the target antigen known but its sequence has been determined. Brocke and colleagues [23] have demonstrated that the T-cell response of DR3+ patients is directed against a epitope defined by AchR peptide 257-269, while DR5+ populations recognize the 195-212 peptide. This condition is similar to the experimental allergic encephalomyelitis (EAE) model, in which an understanding of the target epitape(s), rather than the class II molecule, could provide the basis for specific intervention. One of the best animal models for autoimmune disease is EAE. This is an inflammatory demyelinating condition induced in mice by injection of myelin basic protein (MBP) or its MBP-derived peptides 124,251. The disease is mediated by CD4+ T cells that recognize the acylated amino-terminal nonapeptide (AC 1-9) of MBP bound to a specific class II molecule. Different strains of mice (different class II haplotypes) respond predominantly to different regions of the MBP molecule but produce the same condition. Coinjection of competitor and encephalitogenic peptides can prevent the disease via blockade of the MHC binding site by the competitor peptide [26,27]. These studies demonstrate that it is possible to design and administer soluble peptides capable of MHC-selective inhibition of Tcell activation and autoimmune reaction. Therefore, MHC blockade represents a potential approach to peptide-based passive immunotherapy. Other approaches involve the use of monoclonal antibodies (mAbs) directed against disease-associated MHC antigen, TCR, or the CD4 molecule on T cells. Experimental models of systemic lupus erythematosus (SLE), RA, MG, cutaneous T-cell lym-

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phoma, and EAE using anti-CD4-mAbs have been successful in preventing and reversing ongoing disease as well as diminishing the rate of relapse. However, the immunosuppressive effects were often nonspecific [28]. Animal studies using mAbs directed against disease-associated MHC class II antigens have also been encouraging [29]. Two obstacles limit the potential applicability of this form of immunotherapy: (1) lack of humanized anti-MHC antibodies (available xenogeneic antibodies would be highly immunogenic), and (2) anti-MHC class II antibodies would theoretically result in nonspecific immunosuppression. An interesting feature of the EAE model is the ability of antigen-specific T cells to transfer the disease to a second animal. A large inoculum of activated T cells capable of recognizing myelin will produce a rapidly progressive encephalomyelitis. A smaller inoculum produces a milder disease process characterized by exacerbations and remissions, and formalin-treated populations of activated T cells are capable of immunizing the animal to EAE [30]. This prompted investigators to consider developing a vaccine for active immunization against the autoreactive T cells using the TCR as the target antigen. A TCR-derived peptide was capable of inducing a T-cell-mediated immune response to itself, and such T cells were capable of transferring protection against EAE [31,32]. Extension of these findings to active immunization projects for other autoimmune diseases is predicated on two conditions: (1) the diseases are the result of activation of a dominant, oligoclonal T-cell population and (2) the relative structure of the TCR is known for each disease.

CONCLUSION As our understanding of the pathogenesis of these various autoimmune diseases becomes more sophisticated and the critical molecular interactions are more clearly delineated, it will become feasible to design specific immunotherapeutic interventions. The fundamental principles of the pathogenesis of autoimmune disease are as follows: (1) autoimmune disease results from a failure in discrimination between self and non-self, (2) the effector common to many of these diseases is the autoreactive T cell, (3) certain HLA haplotypes are associated with increased susceptibility to autoimmune disease, and (4) discrete domains of hypervariability within the MHC class II molecule appear to represent the “susceptibility determinant” for many autoimmune diseases. Several approaches to immune therapy are under active investigation. The ideal intervention must be targeted to the specific autoantigen or its restricted

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@

a-TCR

mAbs

C&petitor

c-MHCllmAbs

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Peptide

Figure 4. Proposed mechanisms for immunotherapy. Monoclonal antibodies (mAbs) directed against specific components of the antigen presentation-recognition complex or competitor peptide fragments: A. Anti-MHC class II mAbs. B. Anti-T-cell receptor mAbs. C. Anti-CD4 mAbs. D. Competitor peptide fragments. Note that the peptide may compete for binding at either TCR or CD4.

presenter-effector mechanism and thereby avoid the nonspecific generalized immunosuppression induced by current therapeutic agents. Furthermore, the treatment itself must be protected from the defense system to avoid the problem of anaphylaxis and anti-idiotype responses. Current experimental models for autoimmune disease have variously employed T-cell activation, competitive peptide blockade, and mAbs against TCR, CD4, and MHC class II proteins (Figure 4). The potential exists for major advances in the treatment of autoimmune diseases. The challenges are now to refine our understanding of both the pathogenic molecular mechanisms and current technology in order that we might look to the future for specific intervention in human autoimmune disease.

ACKNOWLEDGMENT We wish to thank Ms. Cheri Vice. Ms. Theresa Varnedoe, for their help in the preparation of this manuscript.

and Mr. Rod W. Powers

REFERENCES

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encephalomyelitis.

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PK, Winchester RJ. Class II in rheumatoid arthritis. Ar-

Autoimmune disease and the major histocompatibility complex: therapeutic implications.

A hereditary basis for the predisposition to several autoimmune diseases has long been suspected. A relationship between diseases and genes that encod...
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