Journal of Autoimmunity (1991) 4,97-l 12

Immunogenetic Features of some Cases of Immune-mediated Skin Diseases

Frank C. Arnett The Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas Medical School at Houston, Texas, USA (Received 31 January 1990, accepted 26 September 1990)

Introduction Immunological mechanisms are increasingly being recognized as underlying a variety of human skin diseases. In several of these disorders circulating autoantibodies and/or immune complexes have either been directly implicated as causing or are strongly associated with the characteristic cutaneous manifestations. In addition, increased frequencies of certain genetically-determined major histocompatibility complex (MHC), especially HLA class II antigens, have been observed. The MHC is known to play a central role in the immune response, and the fact that certain MHC polymorphisms predispose to aberrant immune responses leading to disease states is an important clue to underlying pathogenesis. This review will focus on current knowledge of the genetic fine structure of the MHC and the status of HLA associations with several immunologically-mediated diseases of the skin. MHC: overview The MHC genes map to the short arm of human chromosome six as three major groups of functionally distinct loci, HLA class I, II and III (Figure 1) [l-3]. Both HLA-class I and II molecules, being members of the immune ‘supergene’ family, are structurally similar to immunoglobulin and possess two extracellular domains, the most distal of which functions to bind and present antigen [4,5]. The HLA-class I Correspondence to Frank C. Amett, Houston, Texas 77225, USA.

MD, University of Texas Medical School, PO Box 20708, 97

0896-8411/91/010097+

16 $03.00/O

0 1991 Academic Press Limited

Figure 1. Molecular regions are shown.

map of the major histocompatibility

DPwlDPw6

HLA-D

Gloss lx

DQwlDOw9

complex

DRIDRwl6

A

IIt

DRa52c

DRw52a DRw52b

Bf

c2

genes on chromosome

E

21 -OH

class

2000

B

HLA

kb

I

C

HLA

six. HLA-class

III

TNF

Class

I

E

HLA

4000

I I

A

HLA

kb

I, II and III genetic

I

Immune-mediated skin diseases

99

genes include HLA-A, -B, -C and -E loci which encode glycoproteins co-expressed with 82 microglobulin (class I molecules) on all nucleated cells. Class I molecules present processed antigens to the T-cell antigen receptor on CD8 positive cytotoxic T cells. The HLA-class II region includes HLA-DR, -DQ and -DP genes which encode the alpha and beta chains of heterodimers (class II molecules) expressed on macrophages, B lymphocytes and activated T lymphocytes. Class II molecules present processed antigens to the T-cell antigen receptor on CD4 positive helper T cells [l, 4,5]. The HLA-DR alpha gene (DRA) is invariant, and HLA-DR beta (DRB) alleles confer all the DR polymorphisms, whereas both the DQ alpha (DQA) and DQ beta (DQB) genes are polymorphic [l-3]. Thus, the potential exists at DQ for the formation of trans-associated DQcl/8 ‘hybrid’ molecules from each parental haplotype [6,7], a phenomenon which may explain high relative risks for certain heterozygous DQ combinations in diabetes mellitus [S] and in the Ro and La autoantibody responses [9-121. HLA-DP alpha (DPA) is not very polymorphic, while DP beta (DPB) has multiple alleles [ 131, HLA-class III genes encode the structural proteins for the complement system components C2, C4A and C4B, and factor B, as well as tumor necrosis factor (TNF) and the steroid hormone 2 1-hydroxylase [ 14,151. HLA antigen associations with the diseases to be discussed include primarily HLA class II and class III alleles. Linkage disequilibrium is a very important concept for understanding HLA allele {antigen) correlations with disease. HLA alleles of different loci should occur together no more often than by chance alone, i.e. frequent recombinational events between HLA loci (overall 2% per mating) over time should have distributed these alleles randomly. That is not, however, what is observed in the population. Certain HLA alleles tend to occur together in different ethnic groups on what has been termed ‘extended haplotypes’ [16]. For example, linkage of HLA-Al, B8, Cw7, DR3 and DQw2 is a common combination or haplotype found in Caucasoids of Western European descent. On this same haplotype a deletion of the C4A gene resulting in partial C4 deficiency (C4A*QO) is found [17]. Moreover, multiple autoimmune diseases have been associated with this extended haplotype in Caucasoids [ 181, and the evolutionary explanation for its existence remains unclear. Multiple examples of linkage disequilibrium, usually different, exists for each racial and ethnic group. Thus, it should be understood that an HLA association with HLA-B8 and/or DR3, for example, does not necessarily mean that either of these alleles is primarily involved in disease predisposition; it is just as likely that another linked allele such as DQw2 (DQa or DQP) or C4A”QO is the primary disease-conferring gene. One approach to circumventing the problem of linkage disequilibrium and locating the responsible locus is to search for an allele or an epitope shared by several alleles common to the same disease in patients of different racial or ethnic backgrounds. Examples where this has been useful are discussed subsequently in the sections on lupus erythematosus and pemphigus vulgaris. MHC: molecular genetics Two recent advances now permit more in-depth associations at the molecular level.

analyses of HLA

and disease

100

F. C. Arnett

The first of these involves extensive cloning and sequencing of most of the MHC genes over the last 5 years. These studies at the DNA level have revealed more extensive polymorphism than was apparent from serologic HLA typing. Multiple subtypes of previous serologically defined HLA-DR, -DQ and -DP alleles have been defmed by restriction fragment length polymorphisms (RFLP) [l, 19, 201 and nucleotide sequencing [21]. Sequence-specific oligonucleotide probes can now be constructed which can detect a one-base pair difference and may provide an alternative method for HLA typing, especially in conjunction with application of the polymerase chain reaction to amplify small regions of DNA [22,23]. Determination of the nucleotide and, in turn, amino acid sequences of HLA-DR and DQ molecules has revealed that most of the polymorphisms between different alleles reside in three hypervariable or diversity regions [21] (Table 1). Moreover, there are ‘families’ of DR genes which appear to have arisen from common ancestral alleles via a series of recombinational and/or gene conversion events. [24,25] HLADQ alpha and DQ beta alleles each show similar evolutionary relationships despite different linkages to each other and to more distant DR genes [26,27]. A second major advance has been the determination by crystallography of the 3-dimensional structure of an HLA class I molecule (HLA-A2) by Bjorkman et al. [28,29], and, based upon homologies between HLA-class I and II, a proposed model for the structure of class II antigens (Figure 2) [30]. The most external domain of HLA molecules, encoded by the first exon, is configured as a floor of beta-pleated sheets surrounded on each side by alpha helices. This structure provides a ‘groove’ or ‘cleft’ in which the relevant peptide antigens are bound. Amino acids lining the groove are available for interaction with the peptide, while those directed externally may bind with the T-cell receptor. The amino acids of the first and second diversity regions map within the antigen-binding cleft, while those of the third hypervariable region appear externally on the alpha helices in positions where they could bind to the antigen, the T-cell receptor, or both [30]. Thus, the localization of disease-associated amino acid residues onto this model may provide some clues as to the physical mechanisms involved in an abnormal immune response, vis a vis interactions among MHC, peptide and T-cell receptors. Thus, recent technological advances have now allowed HLA and disease associations to enter a new phase [31]. With the appropriate studies, the actual MHC alleles and their amino acids relevant to an abnormal immune response can be defined. The next phase will need to address the physical associations [32,33], including relevant conformational epitopes, between MHC molecules and autoantigens, as well as possible T-cell receptor contributions. Lupus erythematosus Systemic lupus erythematosus (SLE) is a clinically and serologically heterogeneous disease. Observations that nearly 10% of cases were familial and that approximately 70% of monozygotic twins showed concordance for disease suggested a genetic contribution (reviewed in [34]). Based on the human twin data and studies of murine models it was predicted that multiple genes were involved [35]. The first genetic marker reported for susceptibility in Caucasoids was HLA-B8 [36,37]. Subsequent studies have confirmed this association but have shown that it was marking the HLA-

40

50

60

70

80

90

(--QQD_y------------BDIY-_-DL--_-------_--___--~

(~___QQ~_~__---______~-~IY--_N___---_-___-___----__----~_~-----_____-~-___-___~

DR2a/w2

DR2a/w12 DR2a/MN2

-

(___--EV_~----------L-E-RV___--A-Y___------_____----__-----R_-_____-____~_~--~--~

DRwlO

____

G__--_--_--)

____________)

____

-----)

alleles (from [21 I). Note the hypervariable regions corresponding among DRw52 family versus DRw53, DR2, and DRl, DRwlO

(____~Q~_~---------__LE-CIY---_S__---_-_------_-______--__--------_____~--__~~_-~~--~

(---~Q~-~--____--__~-pcIy----~__-_____-----_----___-__---____~_---_____)

DRl

--_-______-----_----I--_A-_____-___A__-_----)

First domain amino acid sequences of the common HLA-DRBl and 57-86 (third). Also note similarity of sequences of DRBl sequence. Numbers at top indicate amino acid position.

_____

_--v--s----I--D--GQ__v_____G

_-_-_______

DRlS

______

(_--~Q~_~---_---~-~_~IY--_N-----__------~___--~-_~---~_-~__~___”____-G-----_)

DR7/Dwl

DR9/

(c--QQD_Y___-_----H_I-GIY____N

(____WQG-YK----_-_-__Q-_E-L-Y--_F----_-

DR4/Dw15 ______

(_---Q~-~--___----------YH--_--_-----_--___------~-_-------___-----___---___~~

____

(__--Qv_H-----__--_-_---y&.---------___

(-----QV-H--______--_-YH--___-_______-------__--_~__D~-_E_----_-----_----_)

DR4/Dwl4

DR4/Dw13

__---_----_K-______

to positions 9-13 (first), 25-38 (second) families of molecules. cons=consensus

Family

DRI, DRwlO

Family

DR2

Family

DRw53

(____ -QV_H--------____-my’-----_---_-

DR4/Dw4 _____

(----YST-----_---------_--N--------_F_-_----____-~-D~___---___~--__~

DRw6/Dw18

(---Q~-~-___--_---_-YH--_-________-_-------_----~-_~~-___----_------_--_~

~--_YST--____-____-_-----N_________~__-------------___-_------__-~--__-__~

DRw6/Dw16

DR4/DwlO

Family

(----YST---___----__----___--~-___--F____-_--A--H_------R-__~____-__-----_____~

)

DRw61DW9

G

DRw52 _____

DRw8/Dw8

-F--D--L___

(____YSTG--Y-__--________-----------____S--

DRS/Dw5 S ____

(_---_YST---___---__-__-Y______-----_~_------E-__----~-D~__-----__-----__~_~

(__-YST----_---_----_Y--------F-_-____--E-----F--D~_____--__~-~~-~

DR5/Dw5 M

cons

(_---YST-----------_E-__----N----_____--------__-----K_GR__N_-_____~-_~___~

30

DR3/Dw

20

RFLB-KSECHFFNGTERVRFLDRYFHNQEEYVRFDSDVGEY~VTELGRPDAEY~SQKDLLEQR~VDTYCRHNYGVVESFTVQRR (_---YST-----_--_Y_---_----N-___---_F__-_-------__---__K-GR_N---_--____-__~

10

alleles

DR3/DW3

6

Table 1. Amino acid sequences of HLA-DRBl

102

F. C. Arnett

Figure 2. Proposed structure of HLA-class II molecule based on Bjorkman ez al. [28,29] and Brown er al. [30]. N =amino terminal for a (alpha) and p (beta) chains. Numbers indicate amino acid residues. The first hypervariable or diversity regions in each chain map to residues 9-13, the second to 25-38, and the third to 57-86.

B8, DR3 extended haplotype [38-40].

In addition, HLA-DR2 was also increased in Caucasian SLE patients in several studies [38-40]. Overall, by serologic HLA typing techniques, approximately 75% of SLE patients carry HLA-DR3, DR2 or both. The relative risks conferred by each of these alleles were relatively low (approximately 3). Investigations of black Americans with SLE generally showed only weak correlations with HLA-DR2 and/or DR3 or no HLA frequency disturbances compared to racially matched normal controls [41]. Hereditary deficiencies of several complement components, including C2 and C4 which are encoded from MHC class III loci, were also associated with SLE [42-451. The C2 deficient allele was found to be carried on an HLA-A25, B18, DR2 haplotype, but only approximately 6% of patients had heterozygous or homozygous C2 deficiency [45]. Similarly, total C4 deficiency which requires four non-functioning genes (homozygous C4A and C4B deficiency) and which nearly always results in SLE, is exceedingly rare [44]. On the other hand, partial deficiency of C4, primarily due to null alleles (QO) of the C4A isotype, is common. C4A null alleles have been reported in over 50% of white SLE patients [42-44] and also appear to be in excess in blacks with SLE [43,46]. This association has been confounded, however, because the most frequent C4A null allele, that of a C4A gene deletion, occurs on the HLAB8, DR3 haplotype [ 171. Nonetheless, studies in B8/DR3 negative whites, black and

Immune-mediated

Young age nephritis molar rash bullae

skin diseases

103

onset

Figure 3. HLA associations with autoantibody subsets of systemic with permission Rheum. Dis. Cl. N. Amer.) 1751.

Old age onset sic03 complex photosensitive rash (SCLE) less nephritis neonatal lupus vasculitis

lupus erythematosus.

(Reproduced

Chinese SLE patients have demonstrated that C4A null genes are still associated with disease [43, 46-481. In fact, C4A null alleles remain the strongest genetic risk factors for SLE in American blacks [46]. An explanation for how a partial deficiency of C4A and not C4B predisposes to an autoimmune disease remains speculative. It has been shown that the C4A isotype binds more avidly to amino and C4B to carboxyl groups [49]. Thus, C4A should be more effective in eliminating immune complexes than C4B and its loss could promote ineffective immune clearance. The mechanism underlying this association, however, remains to be experimentally defined. Over the last decade, autoantibody subsets of lupus have been well characterized [34, 40, 50-531. When SLE is approached in this manner, more clinically homogeneous subgroups become apparent and genetic associations become stronger (Figure 3, Table 2). Regardless of its clinical setting, the anti-R0 (SS-A) response, often accompanied by anti-La (SS-B), is more strongly associated with HLA-DR2 and DR3 than are their parent diseases. Moreover, patients with the highest Ro and La autoantibody levels were typically heterozygotes for DQwl/DQw2 which are linked to DR2 and DR3, respectively [9, lo]. Ro autoantibodies occur in SLE (50%) [lo], subacute cutaneous LE (SCLE) 80% [50], and primary Sjbgren’s syndrome (80%) [54,55]. Anti-R0 negative patients with these diseases do not show significant excesses over normal controls. Thus, it appears that the MHC genes are actually more important in determining these immune responses than in initiating the underlying disease. In turn, these autoantibodies are likely to be participating in the expression of the autoimmune disease process. This is most strongly suggested by the neonatal lupus syndrome where passive transfer of maternal anti-R0 or La into the fetus is associated with a rash similar to SCLE or congenital heart block. The mothers are almost uniformly HLA-DR3 positive while the HLA status of the infant appears to be irrelevant [52,53].

104

F. C. Arnett Table 2. HLA associations with immune-mediated

Disease

Primary MHC alleles

skin diseases Critical first domain amino acids

Lupus erythematosus

C4A*QO

Undefined

Ro/La autoantibody subsets

DQG DQP2 DQ’& DQP6

Undefined

Anti-dsDNA

DR2 or DQw6

Undefined

Anti-EBA (bullae)

DR2 or DQw6

Undefined

Anti-Sm, RNP

?DR4

Pemphigus vulgaris

DR4 (DwlO) DQwl.19

DRP positions 67-71 DQP position 57

Pemphigus foliaceus

DRl, DQwl (DQwS) DR4, DQw3

Undefined

Epidermolysis bullosa acquisita (EBA)

DR2, DQw6

Undefined

Dermatitis herpetiformis

DQw2

Undefined

Dl’wl ?DPw3

DPP positions 56,57 and 69

The genetics of the Ro/La autoantibodies can now be better approached at the molecular level. Previous studies were all based on serologic HLA typing. A major unexplained phenomenon was the lack of any consistent HLA correlations with these same antibodies in black patients. In general, a disease-conferring gene should cross the racial barrier and should be present in all individuals with that immune response, unless it is genetically heterogeneous. Reveille et aE. recently examined HLA-DR and DQ genes using RFLP in 104 white and black patients with Ro antibodies [ 11,121. In Caucasians, the same linked alleles DR3, DRw52, and DQw2 were increased. It has recently been found that HLA-DR3 has several subtypes which vary little at their sequence levels [l, 561 (See Table 1). However, the Caucasoid DR3 or DRwl7 is linked to DQw2.1, while the black DR3 or DRwl8 is linked to DQw4 [ 1,561. In the black patients studied by Reveille et al. [ 11, 121, the Caucasoid DR3 (DRwl7) along with DQw2.1 were increased, but not the black DR3 (DRwl8) with DQw4. This suggested significant Caucasoid racial admixture in the blacks. Most significantly, there was also a strong excess of DQw6 (formerly a component of DQwl) and DQw2.1 heterozygotes in both racial groups. Taken together, these findings suggested that DQ genes rather than DR were primarily associated with Ro and La antibodies. It should be recalled that DQ alleles are encoded by polymorphic alpha and beta chain genes, DQw2.1 by DQa2 and DQP2, and DQw6 by DQa6 and DQP6 chain genes. It is also important to realize that each of these DQa and DQP chain genes may be represented on different DQ alleles on different HLA

Immune-mediated

HLA-DP AI

q n

HLA-DO El

mxm

IXI

Al

81

BI

a2

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DR3

X

a6

CLASS

HLA-DR

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DR2

lll

62

83

III

skin diseases

105

HLA-8

Al C4A*QO //

DR52 111

/I

87

I

//

88 I

87

I

Figure 4. The two major HLA haplotypes (HLA-B8, DR3 and HLA-DR2) and their linked genes, associated with the Ro and La autoantibody responses. The strongest correlations are with the ‘tram’ combinations of DQa2/DQp6 and DQa6/DQp2. X = recombinational ‘hotspot’ between HLA-DP and DQ. C4A*QO indicates a deletion of the C4Aand 21-OHAgenes. Each of DQa, DQp2, DQa6 and DQP6 can occur on other HLA haplotypes and thus permit similar ‘cis’ or ‘trans’ associations.

haplotypes [ 1, 21, and that these are especially different in black individuals. An analysis was then performed of individual and then combinations of these relevant DQ genes. Indeed, 97% of white and 88% of black patients with Ro and La antibodies had DQa2 or a6/DQP2 or /36‘cis’ or ‘tram combinations of these alleles [12] (Figure 4). The ‘trans’ combinations of DQct6IDQfi2 and DQa2/DQP6 conferred the highest relative risks as compared to ethnically matched controls, as well as to SLE patients without Ro antibodies. These data suggested at least a two gene effect from HLA-DQ with a contribution from each parental haplotype. In patients with anti-Rio without anti-La, findings were similar in two-thirds. In the remainder, especially blacks, DQa3.8 which is nearly identical to DQa2 in amino acid sequence, DQP2 alone or DQP3.2, was present. Thus, a very restricted number of DQa and DQD chain genes appear to be associated with these immune responses (Figure 4). No genetic differences could be found between those with SLE versus Sjogren’s syndrome. The mechanisms underlying these observations remain to be elucidated. It is possible that the ‘trans’-associated DQa2/DQP6 and DQa6/DQP2 are forming ‘hybrid’ heterodimers which promote these autoimmune responses more powerfully than the ‘cis’-associated molecules DQa2/DQp2 and DQa6/DQfi6. It is also possible that the additive effects of several different immune responses, represented on each of these chains, may be playing a role. In subsequent studies, Reveille et al. have examined a possible role for HLA-DP alleles in these patients and found no DP associations (unpublished observations). Similarly, the C4A*QO state does not correlate with the anti-R0 response, but only with SLE itself. Studies of anti-R0 prevalence in families have shown that 21% of first-degree relatives of probands with SLE or Sjogren’s syndrome, regardless of their own antiRo status, manifest these antibodies compared to only 3-6% of normal individuals and their relatives [57]. Genetic analyses indicate that a dominant non-HLA linked ‘autoimmunity trait’ must first be present onto which the relevant HLA haplotypes (DR2 and DR3 with their linked DQ alleles) are then superimposed. Therefore, based on the studies of unrelated anti-R0 positives and these families, it appears that at least two MHC genes, DQa and DQP, usually from opposite haplotypes, and a non-MHC gene(s) are necessary for this abnormal autoantibody response,

106 F. C. Arnett

Pemphigus vulgaris andfoliaceus Pemphigus vulgaris and foliaceus are bullous diseases caused by autoantibodies against cell surface components of keratinocytes which destroy intercellular adhesion. In pemphigus vulgaris, the autoantibodies target a complex of three polypeptides of 210 kD, 130 kD and 86 kD (the vulgaris complex), while in pemphigus foliaceus they are directed to 260 kD, 160 kD and 85 kD polypeptides (the foliaceus complex) [58]. It has recently been demonstrated that the 160 kD peptide of the foliaceous complex is desmoglein, while it is proposed that the 85 kD peptide of both complexes is plakoglobin [58]. Unlike lupus erythematosus in which there are multiple autoantibody responses, the pemphigus disorders probably result from a rather restricted number of immune responses. Pemphigus vulgaris has been associated with alleles present on the HLA-AIO, B38, DR4, DQw3.2 haplotype, a gene cluster very common among Jewish peoples [58-631. In individuals lacking this DR4 haplotype, HLA-DRw6 is usually found. HLA-DR4 has for some time been known to be heterogeneous, based upon a variety of subtypes defined by mixed lymphocyte culture. The molecular basis for the different subtypes has recently been shown to result from nucleotide and amino acid sequences in the third diversity or hypervariable region of the DRBl gene (Table 1) [31]. Only theDwlOsubtypeofDR4foundontheAZ0,B38, DR4 haplotypeappears to predispose to pemphigus. Interestingly, Dw4, Dw14 and Dw15 subtypes, but not DwlO, confer susceptibility to rheumatoid arthritis [31], while the linked DQw3.2 (DQw8) beta chain is strongly associated with juvenile diabetes mellitus [31]. It is proposed that the DwlO subtype of DR4 arose from a gene conversion event from the DRw6 allele, and there was initial enthusiasm that these same amino acids in the DRBl gene of DRw6 were also relevant to pemphigus in patients who were DR4 (DwlO) negative [63,64]. Subsequent studies, however, revealed the presence of a rare DQP allele (DQ81.9) linked to DRw6 which was present in 13 Israeli patients with pemphigus vulgaris and in only one of 13 DRw6, DQwl-matched healthy, Israeli controls [65]. The critical amino acid difference between the susceptibility and non-susceptibility DQwl alleles appeared to be at codon 57 where Asp (GAC) was present rather than Val (GTT) or Ser (AGC). Thus, two susceptibility alleles, DwlO and DQwl.9, with different sequences have been found as the ‘epitopes’ critical to the pemphigus vulgaris autoimmune response (Table 2). The mechanisms underlying these associations remain to be defined. Studies of HLA associations with pemphigus foliaceous are few. A recent study of 48 Brazilian patients by serologic typing revealed increased frequencies of DRl, DQwl and DR4, DQw3 and decreased frequencies of DR3, DQw2 andDR7, DQw2 alleles [66]. While molecular studies remain to be reported, it could be speculated that a relevant epitope resides in the third hypervariable region of DRBl, where DR4 (Dw14) and DRl share the same sequence (Table 1).

Epidermolysis

Bullosa Acquisita

(EBA)

EBA is another bullous disease in which a different autoimmune response appears to be involved, one targeted against components of type 7 procollagen. Gammon et al. [67] recently demonstrated a striking association of HLA-DR2 with EBA in both

Immune-mediatedskindiseases

107

white and black patients. In addition, lupus patients with bullous lesions were also found to possess the same autoantibody and to be nearly uniformly HLA-DR2 positive [67].

Dermatitis

herpetiformis

(DH)

DH is another blistering disease which is strongly linked to gluten-sensitive enteropathy (celiac disease). Granular deposits of IgA are typically found at the dermal-epidermal junction. HLA-Al and B8 (54%) were initially found to be increased in classic DH patients but not in those whose skin biopsies revealed linear rather than granular IgA deposits [68]. Later, HLA-DR3 which is in linkage disequilibrium with HLA-Al and B8 was found in over 90% of DH patients [69, 701. In HLA-DR3 negative patients, HLA-DR7 was noted. Moreover, the HLA-DR3/DR7 heterozygous state was found to confer a very high relative risk for the disease [71, 721. HLA-DR3 and DR7 are both linked to DQw2. Most studies now find that 100% of DH patients are DQw2 positive. The likely locus for susceptibility is the DQP2 gene since this is shared by DR3 and DR7, while their DQa2 alleles are different. More recent data suggest an additive effect from HLA-DP alleles in both DH and celiac disease. Hall et al. [73] have reported increased frequencies of HLA-DPwl (and possibly DPw3) in DH patients, especially those demonstrating IgA antibodies to dietary proteins. Bugawan et al. [74] have described increased frequencies of DPw4.2 and DPw3 in patients with celiac disease. Using oligonucleotide probes to define these DP alleles, they proposed that polymorphic residues at DPB positions 56,57 and 69 may be critical in disease susceptibility. It should be commented that linkage disequilibrium between the DP and DQ subregions is minimal because of a recombinational ‘hotspot’. Thus, these data suggest additive class II effects from HLA-DQ and DP in this disease.

Other genetic loci

A search for additional genetic loci contributing to these diseases is also desirable. Because of the close interaction of MHC with the T-cell antigen receptor (TCR), a role for TCR gene polymorphisms should be pursued. Initial reports of a deletion of the TCR beta gene in NZW mice, an inbred strain which when mated with the NZB stain results in murine SLE, were suggestive; however, subsequent studies have found no evidence that this genetic defect contributes to disease (reviewed in [75]). Preliminary reports of TCR gene polymorphisms with human SLE have been negative; however, these studies have all utilized constant rather than variable gene probes [75]. A genetic requirement for a specific TCR gene has been found for type II collagen-induced arthritis in mice [76], and an increased frequency of a TCR alpha RFLP has been reported in human rheumatoid arthritis [77]. Immunoglobulin genes may also be important to these immune responses associated with disease. Shared idiotypes on certain autoantibodies (anti-DNA and rheumatoid factor) in family members and in unrelated individuals with SLE or Sjogren’s syndrome suggest a contribution from Ig loci which are not MHC linked (reviewed in [75]).

108 F. C. Arnett Recently, a polymorphism of the tumor necrosis factor (TNF) gene and reduced circulating levels have been described in the NZB/NZW Fl model of SLE [78]. Preliminary evidence from the same group suggests that decreased TNF levels are linked to HLA-DR2 haplotypes in humans (C. Jacob, personal communication). Finally, an underlying non-HLA linked genetic trait common to many autoimmune diseases has been suggested by large family studies [79]. Pursuit of the nature and location of this purported gene will also be necessary before the genetics of autoimmunity are fully understood. References Testing. 1989. B. DuPont, ed. Springer-Verlag, New York 1. Histocompatibility 2. Immunogenetics and Histocompatibility 1989. B. DuPont, ed. Springer-Verlag, New York 3. Hardy, D. A., J. I. Bell, E. 0. Long, T. Lindsten, andH. 0. McDevitt. 1986. Mapping of the class II region of the major histocompatibility complex by pulsed-field gel electrophoresis. Nature (London) 323: 453-455 4. Kimball, E. S. and J. E. Coligan. 1983. Structure of class I major histocompatibility antigens. Contemp. Top. Mol. Immunol. 9: 1 5. Giles, R. C.>_andD. J. Capra. 1985. Structure, function and genetics of human class II molecules. Adv. Immunol. 37: l-71 6. Charron, D. J., V. Lotteau, and I?. Turmel. 1984. Hybrid HLA-DQ antigens: molecular expression. In Histocompatibility Testing. 1984. E. D. Albert, M. P. Baur, and W. R. Mayr, eds. Springer-Verlag, Berlin. pp. 539-543 7. Giles, R. C., R. Demars, C. C. Chang, and J. D. Capra. 1985. Allelic polymorphism and transassociation of molecules encoded by the HLA-DQ subregion. Proc. Nat. Acad. Sci. USA 82: 1776-1780 8. Nepom, B. S., D. Schwartz, J. P. Palmer, and G. T. Nepom. 1987. Transcomplementation of HLA genes in IDDM. HLA-DQa- and P-chains produce hybrid molecules in DR3/DR4 heterozygotes. Diabetes 36: 114-l 17 9. Harley, J. B., M. Reichlin, F. C. Arnett, E. L. Alexander, W. B. Bias, and T. Provost. 1986. Gene interaction at HLA-DQ enhances autoantibody production in primary Sjogren’s syndrome. Science 232: 1145-l 147 10. Hamilton, R. G., J. B. Harley, W. B. Bias, M. Roebber, M. Reichlin, M. C. Hochberg, and F. C. Arnett. 1988. Two Ro(SSA) autoantibody responses in systemic lupus erythematosus. Correlation of HLA-DR/DQ specificities with quantitative expression of Ro (SS-A) autoantibody. Arthritis Rheum. 31: 496-505 11. Arnett, F. C., W. B. Bias, and J. D. Reveille. 1989. Genetic studies in Sjogren’s syndrome and systemic lupus erythematosus. J. Autoimmunity 2: 403-413 12. Reveille, J. D., M. J. MacLeod, and F. C. Arnett. 1989. ‘Trans’ or ‘cis’ combinations of HLA-DQa2 or a6/HLA-DQp2 or p chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses. Hum. Immunol. 26(Suppl): 54 (Abstract) 13. Bodmer, J., W. Bodmer, J. Heyes, A. So, S. Tonks, J. Trowsdale, and J. Young. 1987. Identification of HLA-DP polymorphism with DPa and DPfi probes and monoclonal antibodies: Correlation with primed lymphocyte typing. Proc. Natl. Acad. Sci. USA 84: 45964600 14. Carroll, M. C., R. D. Campbell, D. R. Bentley, and R. R. Porter. 1984. A molecular map of the major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature (London) 307: 237-241 15. Carroll, M. C., P. Katzman, E. M. Alicot, B. H. Koller, D. E. Geraghty, H. T. Orr, J. L. Strominger, and T. Spies. 1987. Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc. Natl. Acad. Sci. USA 84: 8535-8539 16. Awdeh, Z. L., D. Raum, E. J. Yunis, and C. A. Alper. 1983. ExtendedHLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc. Natl. Acad. Sci. USA SO: 259-263

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Immunogenetic features of some cases of immune-mediated skin diseases.

Journal of Autoimmunity (1991) 4,97-l 12 Immunogenetic Features of some Cases of Immune-mediated Skin Diseases Frank C. Arnett The Division of Rheum...
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