Genetics of autoimmune diseases

R. Winchester
Hospital for Joint Diseases and Division of Medicine, New York University
Current Opinion

of Rheumatology, Center,

Department

Medical

New York, USA

in Immunology

1989, 1:701-707

Introduction There has been a rapid evolution in the approach to understanding the genetic basis of autoimmune diseases. This has primanly resulted from the widespread use of advanced techniques in cell biology, immunology and, most notably, the powerful methods of molecular biology. Progress during this period has principally occurred in unravelling the genetic basis of immune regulation, particularly that encoded by the major histocompatibility complex (MIX). Taken together with parallel studies on the Immune alterations, it is clear that this area is moving towards the delineation of what could be designated as the critical immune recognition event underlying the given autoimmune disease. This review will concentrate on two representative diseases: (1) lnsulir-dependent diabetes mellitus and (2) rheumatoid arthritis, as prototypes where susceptibility to the autoimmune state is determined, at least in part, by particular class II MHC alleles. Some developments in the human leukocyte antigen (HIA)-B27associated class I diseases will be brielly covered. The non-MHC genes involved in immune recognition, notably the T cell receptor and immunoglobulin (Ig) polymorphisms, along with the associated questions of repertoire and tolerance, are now areas of intense activity and they will be brielly mentioned. lastly, various cognate immune systems involved in determining effector aspects of the autoimmune response, such as the complement components and other molecules Involved in acute phase responses, are beginning to be the objects of study using the new methods of reverse genetics to identify relevant genes and their polymorphisms. Studies in systemic lupus etythematosus that may be relevant to this area are also discussed. Figures l-3 provide a brief orientation to the MHC genes and the conformation of their products.

mellitus and rheumatoid arthritis seeks to explain the development of injurious autoantibodies directed to islet cells or IgG molecules. One can presume that a specific immune recognition event involving MHC class II allelic products provides the context for autoantigen presentation to a T cell clone of the CD4 lineage that bears a receptor specific for the antigenic peptide. These T cells then provide help to clones of pre-existing B cells specific for autoantigens that are expanded and differentiated into plasma cells, resulting in the formation of autoantibodies. The T cell component of this immune response is perhaps the more injurious element, at least in the case of rheumatoid arthritis. The central defects underlying autoimmunity of this variety are regulated: (1) at the level of the h4HC allelic product where the ability to specikcally bind and present antigenic peptides is encoded; (2) at the level of the T cell repertoire, which in part is selected in conformity with the various poly morphic MHC products an individual inherits; and (3) by the B cell repertoire. Available evidence indicates that the B cell repertoire that Includes autoreactive antibodies is similar in various individuals and is not the result of defects in Ig germline genes [l]. Accordingly, attention to the genetic basis of autoimmunity is mainly directed to the first two elements in this scheme. The lines of investigation that emerged nearly 15 years ago with the initial associations of susceptibility of insulin-dependent diabetes mellitus and rheumatoid arthritis (for a review of early work see Winchester et al In Advances in Immunology, Academic Press, 1979, pp 221-292) with the then ill-defined serologic or mixed lymphocyte culture-delined markers have now arrived at a reasonable molecular basis for their occurrence that is elegant and simple. In the instance of insulin-dependent diabetes mellitus, the path from serology began with studies of restriction fragment length polymorphisms (RFLP) that delineated two HLA class II genes, one designated HIA DQ3.2, now termed HLA DQw7, that is associated with susceptibility, and another alternative gene, HIA DQ3.1 (DQw8>, that exhibited much the same serologic reactivity, but is not relevant to susceptibility (Kim et al, PYOCNat1

MHC class II-associated

diseases

The underlying paradigm for the genetic basis of autoimmune diseases such as insulin-dependent diabetes

Abbreviations
AIDS-acquired immune deficiency syndrome; HLA-human leukocyte antigen; Ig-immunoglobulin; MHC-major histocompatibility complex; RFLP-restriction fragment length polymorphism; SE-systemic lupus erythematosus; TN&tumor necrosis factor.

@ Current Science Ltd ISSN 0952-7915

701

702

Autoimmunity

Class II

Class ill

TNF

Class

I
D Centromere e -

C4A, C4B B, 21-OHase

r-l
a P I--mm

r----l
BC A Chromosome 6

C2, factor

I,
CB

DP subregion

DQ subregion

DR subregion

1 Jra P a
DZa DO8

I
DX8 DXu 8 u

I
81 $8 P3 a

DPwl

DQ WI DQ w2 DQ w3 DQ w4

DRl DR2

DR ~52 DR w53

D&6

DRw18

Fig.1. The organization of the class II genes of the major histocompatibility complex (MHC). Only the indicated genes make identified products. The cell surface of an antigen presenting cell may have three or four different isotypes of MHC class II molecules encoded by the genes of a single sixth chromosome, the number depending on whether the DRP, gene is functional. The a and 8 chains of each of the subregions DR, DP and DQ effectively combine with only their homologue from the same subregion. With the exception of the DRa chain all of the expressed genes are polymorphic, leading to the possibility of two additional kinds of both DQ and DP molecules arising from the combination of trans encoded chains, bringing the potential maximum number of different antigen-presenting class II molecules to 12 in a DR3, DR4 heterozygote. A DRI homozygote would only have three different species. (See Winchester, In The Textbook of Rheumatology, edited by Kelley et a/., W.B. Saunders, 1988, pp 101-137, for an introduction to immunogenetics that emphasizes autoimmune diseases.) The figure depicts the molecules that bear the serologically defined specificities.
Acud

Sci USA 1985,

1986, 26~299-303;

Med
1987,

144:345350;

Nepom et al, J Exp et aC, Immunogeneticx Michelsen et al, J Clin Invest 1987,
82:81398143; Mortos

152). The next level of research led to sequencing of the relevant chains of the putative susceptibility genes and carefully determining their specific positive or negative association with disease [2]. The critical region of the DQ molecule is currently visualized as the righthand portion of the DC@ chain CC helix. The position is presumably analogous to that of the DRB chain molecule depicted in Fig. 3. The DQ alleles, including 3.2, all contain either valine, alanine, or serine at position 56, while aspartic acid is present at the same position in all of the DQ alleles that are neutral or negatively associated with the disease.

79:1144-l

cleft is altered by the presence of a charged or uncharged residue. The large-scale difference in conformation that this single-residue charge induces can be seen by the effect it has on an epitope located at position 45 [3]. In contrast, the susceptibility DQfi molecules containing the DQ3.2 chain probably do not induce tolerance at the level of the T cell repertoire, and may bind the antigen involved in initiating insulin-dependent diabetes mellitus. The serologic typing Iindings in rheumatoid arthritis had to account for a complex pattern of susceptibility as sociated with DRl and certain alleles in the DR4 fam ily such as Dw4, Dw14 and Dwl5, but not the DwlO or LIw13 varieties of DR4. The most recent studies of this association have been done by Oilier et al. [4] and Nepom et al. [5]. Sequencing of the various forms of DR4 and DRl (Getgersen et al, Proc Nat1 Acud Sci USA
1986, 1985, 83:2642-2646; 82:3405-3409; Bell

This finding of do minant resistance to the development of insulin-dependent diabetes mellitus, as reflected by a negative association, suggests that one inliuence of the polymorphism is on the repertoire of T cells that develops from thymic selection. One can speculate that the distinctive DQ con6guratlon that results from the presence of the aspartic acid tolerizes the individual such that the immune response necessary to develop the disease does not occur. It is likely that the overall relationship of the CL and g chains at this end of the antigen-binding

et al, Pnx Natl Acud Sci LISA

Merryman et al, Artbritzk Rbeum 1989, 32:251-258) and studies on high frequency of reactivity with monoclonal antibody I@ki6 among rheumatoid arthritis patients (ke et aL, Swum znt 1984, 4 suppl:17-23) led to the formulation of the shared epitope hypothesis [6,7] in which susceptibility was explained by the presence of a critical sequence of residues along the rim of the ct helix from positions 67-74 that is found in

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a)

Fig.2. The conformation of the MHC class I antigen binding superdomain of the HLA-A2 molecule as determined by Bjorkman et a/. 1161using X-ray crystailography. An antigenic peptide is presented to the T cell antigen receptor in a cleft of approximately 10 x 10 x 25 Angstroms. The walls of the cleft are composed of CL helices and the floor by (3 pleated sheet. (b) illustration showing where the principal polymorphic residues, shown in black, of the HLA827 molecule are located, emphasizing that different peptides are presumably bound with different affinities through interactions with the amino acid-side chains encoded by this allele.

all of the susceptibility haplotypes regardless of whether they bear the serologic specificity of DRl or DR4, which is in fact encoded elsewhere in the molecule. The critical amino acid sequence associated with susceptibility involves a leucine(67>-glutamine(70)-lysine/arginine(i l) alanine(74). The presence of an acidic residue at position 71 or 74 of the DRf3 chain in an otherwise equiva lent a helix sequence appears to eliminate susceptibility to rheumatoid arthritis [6-8]. The epitope or conformational equivalence hypothesis is readily understood in terms of the patchwork nature

of the class II alleles. Evolutionary relationships principally determine the variation of the first two diversity (hypervariable) regions that are located in the floor of the antigen-binding cleft. These encode many of the serologically detected epitopes that define the DR specilicities. In contrast, the third diversity (hypervariable) region comprising the sequences of the a helical portion of the molecules appear to arise through gene conversion events. These third diversity structures account for the conformational or epitope equivalence of serologitally unrelated specificities. Four studies support the view

704

Autoimmunity
Fig. 3. The
of with the the class the presumptive II molecule model. binding of two Brown organization by analogy that is dis1988, Note

Bjorkman

antigen

superdomain symmetrically

composed 1988, and 332:845450,

posed u and p chains. (See Winchester, et al., Nature who describe the class II

model in greater detail).

that shared sequences found in different haplotypes are associated with epitopes recognized by antibodies or T cell clones [P-12]. Three of the studies [ lO--121 are examples of the third diversity region epitope implicated in rheumatoid arthritis. The importance of this region to the immune response is emphasized by studies on the bm12 mouse where the substitution of three amino acids in the same location of the 01helix abolishes the ability to develop experimental myasthenia gravis and to respond to beef insulin. Moreover, this change creates the ability to respond to sheep insulin (Mengle-Gaw et al, J Exp Med 1984, 160:1184-1194; Ho&man et al, J Eq9 Med 1984, 160:192+1930; Christadoss et al, Immunogenetics 1985, 21:33-38). In the case of rheumatoid arthritis, susceptibility is inherited as a dominant trait, which suggests the interpretation that an individual at risk for developing the disease has a particular abiity to effectively present a particular peptide. This dete rminant selection model further suggests that the inciting peptide or antigen X , as it is termed, has one or two negatively-charged residues that prevent its effective binding to the DRB chains that contain neg ative residues at position 71 or 74 [7]. Peptide binding to the MI-E class II molecule [ 131 has been visualized in terms of an 01helical antigen binding in the MHC 1141. It is an interesting exercise in history to the early papers on serologic associations with rheumatoid arthntis and systemic lupus ~etythematosus (Gibofsky et al, Arti?t-iti R&urn 1978, 21:S134-S138; Winchester et al, 1979; Reinertsen et al, N En@ J Med 1978,299:515-518) and see where in the absence of any sign&ant structural information that particular reagent sera recognized

a disease-related specificity that may, in retrospect, be the disease-related third diversity region epitope distinct from that of the normal typing reaction of the serum. Investigation of the genetic basis of these disorders is now increasingly turning to the T cell receptor. Stamenkovic et al. [ 151 have reported that the T cell lines expanded from different synovial sites in rheumatoid arthntis exhibit the same T cell receptor gene clonal rearrangements. However, issues remain to be resolved because the predominant expanded T cell population in the syrovium of osteoarthritis patients showed similar clonality.

Class I diseases The spondyloarthropathies are characterized by susceptibility associated with class I alleles, notably HLA-B27. Among these disorders which lack autoantibodies, Reitefs syndrome perhaps best fits our notion of an aberrant immune reaction to an infection with a particular gram-negative enteric organism. The Bjorkman model of class I structure [16] greatly clariiies the visualization of the way in which a putative antigen would be bound by the HL4-B27 molecule and presented to a T cell antigen receptor. The understanding of the chemical basis of the six different alleles of U-B27 is now essentially completed [17], and the risk of developing the disorder is conferred by the inheritance of a single B27 al lele [ 181. This, coupled with the lack of a demonstrated dominant resistance HLA allele, suggests that a determinant selection-antigen binding model is the most likely. However, the nature of the autoimmune response, if it in-

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705

existed at all, was perplexing. One had to explain the absence of usual evidence of delayed hypersensitivity lesions characterized by numerous lymphocytes including many CD4 cells, the absence of autoantibodies, complement activation, and leukocytoclastic vasculitis, but the presence of a response to immunosuppressive drugs.
&ed

trated in studies of families with multiple cases of systemic lupus efythematosus [ 271. The role of certain HIA alleles in influencing the production of autoantibodies in either systemic lupus erythematosus or Sj@ren s syndrome continues to receive support. For example, both SSA/Ro and SSB/Ia antibody production have been associated with class II alleles [28,29].

The observation that severe Reiter s syndrome occurred in individuals with acquired immune deficiency syndrome (AIDS) who were predominantly HLA-B27, and after the usual infections [ 191,directed attention to the role of CD8 lymphocytes as the critical T cell lineage involved in the disease. This leads to a paradigm of class I autoim mune diseases involving presentation of an antigen in the context of, for example, HLA-B27 to a T cell antigen receptor on a CD8 lineage T cell. This immune recognition event would be followed either by a cytotoxic attack on the antigen-presenting cell or release of various lymphokines that alter the patterns of gene expression and consequently the function of neighbouring cells. The question of how T cell clones are capable of this autorecognition has been studied by numerous investigators. Zwillich and Lipsky [ 201 have published an excellent review of the notion that molecular mimicry between an epitope of self and a microorganism underlies this loss of tolerance. The observation by Stieglitz et al. [21] that a plasmid encoding a relevant peptide containing the sequence in the HUB27 molecule is of interest. Additional references to this and related areas are contained in the summary of a workshop on the immunogenetics of the rheumatic diseases [ 221.

Non-MHC

genes

RFLP technology is beginning to be applied to aspects of the pathogenesis of autoimmune disease. An interesting example of this approach is the identification of a polymorphism for the serum amyloid P component gene that is sign&a@ associated with the development of the complication of amyloidosis in patients with juvenile chronic polyarthritis [30].

Annotated reading 0
?? e

references

and recommended

Of interest Of outstanding

interest

KOFIERR, DD(ON FJ,THE~FIuXO~L~~AN: The genetic origin of autoantibodies. Itnmunol Today 1987, 8:374-380. The contribution to our understanding of the development of autoreactive antibodies has come from studies of the murine models of lupus. The authors review Aidence that there are no unique germline genes or mechanisms generating antibody repertoires in the autoimmune strains that distinguish them from normal strains. 1.
??

MHC class Ill-associated

disease

Systemic lupus erythematosus presents a particular challenge for understanding the genetic basis of autoimmu&y. It is the prototypic autoimmune disease with a strong polygenic basis (see Hochberg et aL, J Rbeum 1987, 14:867+69; Winchester et al, Arthritis Hwum that is in part related to the class II 1982, 25:83=37) alleles DR2 and DR3 (Gibofsky et UC, Arth-itis Rbeum 1978, 21:S1344138; Gibofsky et al, J Exp Med 1978, 148:1728-1732; Reinertsen et al., 1978). However, there is a strong body of evidence that implicates alleles of the C4A and C4B genes in linkage disequilibrium with the class II alleles as the primary risk factors [23,24]. Presumably these would act to enhance disease susceptibility by deterring the efficiency of the complement system in modulating the fate of antigens. Other investigators emphasize the possibility of interactin between class II and class III genes that result from the inheritance of extended haplotypes [25]. The recent report by Spies et al. [26] concerning polymorphisms of five genes closely linked to the tumor necrosis factor (TNF) loci and HLA-B affords yet another possible mechanism for the genetic basis of MIX-associated autoimmunity. The role of nonMHC factors continues to be studied and is well illus-

to susceptibility and resistance to insulin-dependent diabetes meRitus. Nature 1987, 329:59%03. The paper presents a correlation between the sequence of DQfl chain alleles and either susceptibility or resistance to the development of insulin-dependent diabetes mellitus (type I diabetes mellitus). Interestingly, in both humans and in the NOD mouse, the presence of an amino acid without a negative charge at residue 57 is associated with susceptibility, In contrast, the presence of aspartic acid at this position is associated with resistance to the development of insulin-dependent diabetes
?? e IIdiNS.

2.

TODD JA, BELL JJ, MCDEVI II HO: HLA-DQfi gene contributes

WW, LOTSHAW C, MUNER ECB, -R-JACK N, NEPOM GT: Mutational analysis of the HL4-DQ3.2 insulindependent diabetes mellitus susceptibility gene. Proc Nut1 Ad Sci US4 1989, 86:in press. A detailed analysis of amino acid substitution in the DQ3.2 p chain gene that distinguish this allele from the related DQ3.1 p chain not associated with susceptibility to insulin-dependent diabetes mellitus is presented. Using site-directed mutagenesis the influence of changes at various residues resulted in delining their inlluence on a serologic epitope located at residue 45.

3.

KWOK

??

4.
??

OLLIER w, CARTHY D, CUTBUSH s, OKOYE It, AWAD J, FIELDER A, SIIMAN A, FESTENSTEIN H: HLA-DR4 associated Dw types

in rheumatoid arthritis. Tissue Anfigms 1988, 33:3@37. Using MLC typing and frequency of Dw subtypes of DR4 were determined in patients with rheumatoid arthritis and controls. The preva lence of Dw4 was 49 versus 22.9% in the controls (relative risk 3.21, and the ptwalence of Dw14 was 22.8 versus 2.1% in the controls (relative risk 13.9). The respective B locus alleles associated with the Dw subtypes were B44 and Bw62 for Dw4 and B&0, Bw44 and B27 for Dw14. Dw13 was not signilicantty increased in the patient group.

706

Autoimmunity
5.
??
NEPOM

GT, BYERSP, SEYFRIED C, HFAIEY LA, WMKE m, STAGE HM gen~ associated with rheumatoid D, NEPOM BS: arth&&. A?-tbriti Rbeum 1989, 32:15-21.

us@ o~nudeotide probe typing methods, the frequency of the Dw subtypes of DR4 were determined in patients with rheumatoid arthritis and in controls Dw4 was found in 50 versus 17% of patients and Dw14 in 35 versus 5%. These together accounted for 73% of rheumatoid arthritis cases. The non-DR4 patients had a high frequency of Dw14related sequences supporting the notion of a shared epitope . GREGER~EN PK, SILVER J, WINCHESTER RJ: The shared epitope hypothesis - an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Artbritzk Rheum 1987, 30:120~1213. A formulation simplifying the complex pattern of association of rheumatoid arthritis with SerologicaIly dehned alleles emphasizing that specllic shared sequences in the 3rd diversity region of susceptibility alleles account for the molecular basis of this susceptibility independently from their serologic specificity. 6.
?? e

This study demonstrates that the nucleotide sequences shared by the Dwl4 variety of DR4, and Dwl6 DR encode an epitope recognized by a T cell clone raised against Dwl4. Position 71 seems to be critical for the recognition. Buus S, SETI E 4 COLON SM, MILESC, GREY HM: The relationship between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science 1987, 235:13531366. One of the fascinating developments is that direct measurements can be made of the binding of antigenic fragments such as are derived from egg albumin to MHC class II aUelic products. High tinity binding was necessary but not sufficient for a T cell immune response to occur. 13.
??

The molecular basis of susceptibility to rheumatoid arthritis: the conformational equivalence hypothesis. Springer Semin Immun@atboL 1988, 10:119-139. An extension of the previous shared epitope hypothesis to include the results of the association of DRl with rheumatoid arthritis. Many additional background data are presented. The term conformational equivalence hypothesis was suggested as a substitute for shared epitope hypothesis to emphasize that the envisioned role of the common structure was to bind peptides rather than function as an epitope.
??

7.

WINCHESTER RJ, GRECEREN PK:

ROTHBARDJB, LECHIER RI, HOWL~ND K, BAL V, ECKEW DD, SEKALY R, LONG EO, TAYLORWR, LAMB JR: Structural model of HLA-DRl restricted T ceil antigen recognition. CelZ 1988, 52:515-523. This article depicts the way in which peptides binding to a DRl molecule could form an a helix 1OA in diameter that binds to the MHC class I model. 14.
??

8. me

NEPOM GT, HANSENJA, NEPOM BS: The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin lmmunol 1987, 7:l-7. This study contrasts the D@ chain locus association of insulin-dependent diabetes meUitus and the DRB chain locus of rheumatoid arthritis. Various haplotypes are described, some of which confer conjoint susceptibiity to both diseases. The mechanisms of mutation and recombination underlying the diversity of the haplotypes is informatively discussed. 9.

STA~ENKOVIC 1, STEGAGNOM, WRIGHT KA, CRANESM, AMENTO EP, COL~IN RB, DUQUESNOYRJ, KURNICK JT: Clonal dominance among T-lymphocyte infiItrates in arthritis. Proc Nutl Acad Sci USA 1988,85:117+1183. lnterleukin 2-responsive T lymphocytes were grown out of synovial fragments from 14 patients with rheumatoid arthritis or osteoarthritis. Southern blot analysis of T cell receptor p chain genes in 13 of 14 cult tures showed distinct rearrangements, indicating that each culture was characterized by the predominance of a limited number of clones. This pattern of predominance was not seen with T cell populations from pedpheral blood.

15.

?? e

BERTE CC, TANIGAKI N, Tosr R, GORSKIJ, MACH B: Serological recognition of HLA-DR alkxieterminant corresponding to DNA sequence invoIved in gene conversion. Immune genetics 1988, 27:167-173. An epitope on the 01 and PIII chain recognized by a single antibody is shown to be formed by the same sequence of amino acids. The underlying nucleotide sequence is identical, arguing that a gene conversion event is responsible.
??

BJ&KMAN PJ, SAPERMA, SAMRAOUI B, BENNE~ WS, STROMINGER JI WILEY DC: Structure of the human class I histocompatibility antigen, HLAA2. Nature 1988, 329:506-512. The 3.dimensional model of the class I MHC allele HI&U is presented based on X-ray crystallographic analysis. This notable paper provides a clear insight into the context of antigen presentation to the T cell and gives a notion of the scale of the peptide fragments that serve a5 antigens. No longer will the T cell receptor be portrayed as binding jointly to a large viral particle next to a small HL4 molecule on the cell membrane. 16.
?? e

MATSLNAMA T, WINCHESTERR, LEE S, SHOOKSER 1 NIJIWROUXN A Identikation of the DRwlO DRP I-chain allele as encoding a poIymorphic class II MHC epitope otherwise restricted to DRB z molecules of tbe DRw53 type. J Immunol 1988, 140:537-543. The epitope delined by mAb loW6 is shown to be present on 82 chains of DR4, 7 and w9 haplotypes, and the fil chain of DRw9 and DRwlO haplotypes. This suggests that a common sequence is present in each allele. 10.
??

ROJO S, MARICIO P, HANSEN JA, CH~O SY, IQPEZ DE CASTRO JAL Structural analysis of an HLA-B27 functional varant, B27d, detected In American blacks. J Immunol 1987, 139:33+3401. This analysis completes the structural characterization of the 6 known HLA-B27 subtypes. Their evolutionary relatiomhips are discussed. AI1 HLA-B27 alleles are equivalently associated with the risk of developing spondyiitis.

17.

??

SUREZALMAZOR ME, RUSSELLAS: B27 homozygosity and ankyIosing spondyiitis. J Rbeumutol 1987, 14:302-304. The frequency of B27 homozygosity was determined in 100 patients with B27 positive ankylosing spondylitis. The difference between the observed frequency of homozygosity of 6% and the expected frequency of 2.3% was not significant. Although B27 homozygosity may have some influence on the severity of the disease, it does not increase the risk for ankylosing spondylitis even in families of patients with this disease

18.

??

MERRYMANP, GREGERSENPK, LEE S, SILVER J, NIJRFZROLDAN A, CRAPPER R, WINCHESTERR: Nucleotide sequence of a DRwlO p chain cDNA clone: identity of the third D region witb that of tbe DRw53 allele of the fI 2 locus and as the probable site encoding a poIymorphic MHC class II epitope. J Immunol 1988, 140:2447-2452. The molecular basis of the shared epitope recognized by monoclonal antibody 109d6 is shown to be IikeIy due to a sequence of residues in the third diversity region that is encoded by an identical nucleotide sequence.

11.

??

19.
??

WINCHESTER R, BERNSTEIN DH, FISCHER HD, ENLOW R, SQIOMON G: The co-occurrence of Reiter s syndrrome and acquired

hnmunodeficiency. Ann Intern Med 1987, 106:lF26. The occurrence of severe Reiter s syndrome in patients with AIDS is used as an argument that the immune response relevant to Reiter s sync drome proceeds through a non-CD4 ceII lineage, accounting for the absence of autoantibodies. The CDS lineage is considered the likely cell type because of the relationship of susceptibility to HLA-B27. 20. . ZWIUCH SH, LIPSKYPE: Molecular mimicry in the pathogenesis of rheumatic diseases. Rbeum Dis Clilz North Am 1987, 13:33+352. An excellent introduction to the area of molecular mimicry, with emphasis on a review of contemporary immune mechanisms as they relate to the mimicry hypothesis.

12.
??

SEYFRIED CE, MICKELSON E, HANSENJA, NEPOM GT: A specific nucleotide sequence defines a functional T-cell recognition epitope shared by diverse HLA-DR specificities. Hum frn~ muno1 1988, 211284-299.

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%IEGLIE H, Foshu~~ S, LU%KYPE: Bacterial epitopes invalved in the induction of reactive arthritis. Am J Med 1988, 85:5&58. ~rthritogenic Sbigellajlexneri strains contain a 2-megadahon plasmid, pHS-2, that encodes a 22.amino acid polypeptide encompassing a pentapeptide homologous to part of the polymorphic region of the alpha-l domain of HIA-B27.
21. @ SCHWARK! BD: Proceedings of a symposium: Workshop on the Immunogenetics of the rheumatic diseases. Am J Med 1988, 85:1-61. This supplement is based on a workshop on the immunogenetics of the rheumatic diseases held in June 1988.20 groups summarize recent progress in fields related to the genetic basis of the autoimmune diseases. It is an excellent introduction to the area. 22. 00 KEMP ME, ATKINSON JP, SKANE.S VM, LEVINE RP, CHAPLIN DD: Deletion of C4A genes in patients with systemic lupus erythematosus. An%ritk Z&urn 1987, 30:1015-1022. Class III MHC genes of white systemic lupus elythematosus (SLE) patients were examined using Southern blotting. 9 of 88 SLE patients were C4A null. The C4A gene was deleted from both chromosomes in 8 of the 9 C4AnuU patients. Heterozygous states were detected in 34.5% SLE patients who were not C4A deficient compared with 12.5% controls. Deletions of C4A were observed most commonly as part of the HI&B8:DR3 extended haplotype. 23. 0 24.
??

new cluster of genes within the human major histocompatibility complex. Science 1989, 245216217. Five potentially polymorphic genes, HIA-B-associated transcripts, have been &lent&d in a 435kb DNA segment centromeric to HLA-B by chro~ mosome w&ing techniques. The genes are located in a 16okb region that includes the genes for TNFa and p. The possibility exists that some diseases associated with the B locus HIA alleles could be accounted for by the HIA-B-associated transcript polymorphisms. JONES JV, JONES E, FORSYI-HSJ, SKANESVM, REICHLIN M, MAC~WEEN JM, EASTWOOD S, CARR RI: Familial systemic lupus etythematosus - evidence for sepamte loci controlling C4 deficiency and formation of antibodies to DNA, nRNP, Ro and La. J Rbewnatol 1987, 141263267. A famiIy in which 2 sisters have systemic lupus etythematosus in a sibship of 14 is reported. The a&ted siblings, and 4 other members of their sibship, are haIf nuU homozygotes for the C4A component of complement. 8 of 11 members of the affected sibship are antibody prcducers to ss and dsDNA, and to Ro(SSA), Ia(SSB>, Sm and nRNP. The authors conclude that apart from the MHC several other genes are irvalved in the production of antinuclear antibodies. 27.
??

26. 0

SPIES T, BL~NCK G, BRESNAHAN M, SANDS J, STROMINGER JL: A

BATCHELOR JR, FIELDER AHL WAIPORTMJ, DAVD J, LORDDK,

DAVEYN, DODI IA, MALGITP, WANACHIWANAWIN W, BERNSTEIN R, MACKWOKTH-YOUNG C, ISENBERG D: Pami@ study of the

MADD~SON PJ, ISENBERG DA, GCXJIDING NJ, UDDY J, SKWNER RI? Anti La(SSB) identifies a distinctive subgroup of systemic lupus erythematosus. Br J Rbeumatol 1988, 27~27-31. Anti-La is detected in 39 of 185 lupus patients and is accompanied in variably by anti-Ro. Anti-Ia identifies patients with higher titres of anti-R0 antibodies and is signiticandy associated with HIA-DR3.

28. 0

major histocompatibility complex in HL4 DR3 negative patients with systemic lupus etythematosus. CIin F_q Zmmunol 1987, 70:364-371. A study of 44 cases of SLE, selected because they were DR3 negative. 60% had extended HIA haplotypes with a C4 null allele, compared with 37% of 60 DR3 negative controls. Of 14 non-caucasoid patients analysed, 10 had a C4 null allele. 25.
0

HA=

BR, WONG KL, WONG RWS, CHAN KH, DUNCKIEY H, SERJEANISON SW: Strong association between the major his-

REICHLIN M, HARIJZY JB: Antibodies to Ro(SSA) and the heterogeneity of systemic lupus etythematosus. J Z?beumurd 1987, 14 (suppl 13):112-117. Among the patients with SLE who produce anti-Ro(SSA) are 2 groups, one which produces anti-Ro(SSA) along, usuaIIy in association with HIA DR2, and one which produces both anti-Ro(SSA) and anti-Ia(SSB) usuaUy in association with DR3.

29. 0

tocompatibility complex and systemic lupus etythematosus in southern Chinese. J Rbeumatoi 1987, 14:112&1131. A s&r&ant excess of HIA-DR2 and C4A null aIIe1e.s was found in the patients. An unusual variant of C4B is present in 6 patients and 1 control. The possible role of extended haplotypes was considered in interpreting these results.

Woo P, O BRIEN J, ROBSON M, ANSELL BM: A genetic marker for systemic amyloidosis in juvenile arthritis. Lmzcet 1987, ii:767-768. The authors identify a genetic marker of susceptibility to systemic amyloidosis. A DNA polymorphic site, 5to the serum amyloid P component gene, is SigniIicantIy associated with amyloidosis in juvenile arthritic patients. 30.
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