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Although males with systemic lupus erythematosus (SLE) represent 4—22% of all SLE patients, it may not be appropriate that these cases should be subordinated to females with SLE in terms of most health-related issues. Over the past few decades, some distinctive features of male lupus have been observed with regard to genetic and environmental aspects of sex differences, clinical features, and outcome. In addition, recent insights into sex disparities in this disease have brought forth a few plausible and novel pathogenetic hypotheses. This review discusses these findings and sex disparities in SLE that appear to be especially noteworthy and pertinent to our understanding of male SLE. Lupus (2010) 19, 119—129.

Hysterectomy is one of the most common surgical procedures performed in United States, and currently, one in three women in United States has had a hysterectomy by the age of 60 years. Systemic lupus erythematosus (SLE) is a common autoimmune disease and especially targets women of childbearing age at least 10 times higher than men, which reflects the major role of female sex hormones. In this retrospective study, we evaluate the potential effects of previous hysterectomy in our lupus cohort. Data collected from study subject questionnaires were obtained from the Lupus Family Registry and Repository (LFRR) at the Oklahoma Medical Research Foundation. Hysterectomy data were available from 3389 subjects. SLE patients with a positive history of hysterectomy have been selected and compared with matched lupus patients with a negative history of hysterectomy and healthy controls. Association analyses were performed, and the P values and adjusted odds ratios (ORs) were calculated. SLE patients with a negative history of hysterectomy more likely had kidney nephritis or positive anti-dsDNA than age-matched SLE patients with a history of hysterectomy before disease onset. This effect was independent of ethnicity with an OR of 6.66 (95% CI = 3.09–14.38, P = 1.00 × 10−8) in European patients and 2.74 (95% CI = 1.43–5.25, P = 0.001) in African-Americans. SLE patients with a positive history of hysterectomy before disease onset also had a later age of disease onset ( P = 0.0001) after adjustment for age and race. Our findings support the notion that the influence of female sex hormones in SLE and various clinical findings are tremendous and that surgical menopause such as this could significantly affect the outcome of disease and clinical manifestations.

Summary It is well known that sera of patients with systemic autoimmunity contain autoantibodies to nuclear antigens. It is also known that patients with systemic autoimmunity have an increased risk for the development of tumours. Interestingly, tumour patients frequently develop autoantibodies and there is a growing list of potential tumour-associated antigens. It is, however, not known whether or not patients with systemic autoimmunity also develop antibodies to tumour-associated antigens. Here we describe the development of a novel multiprotein array allowing us to screen for autoantibodies to 30 different tumour-associated antigens in parallel. Using this novel assay, we found that the frequency of autoantibodies to the selected tumour-associated antigens is increased between 2- and 14-fold in patients with systemic autoimmunity compared with an age-matched control group.

The transfer of biomolecules to a membrane support, referred to as blotting, has been an integral part of life sciences research. Southern first described the transfer of DNA to nitrocellulose membrane in 1975 (Southern blotting), spawning methods to transfer RNA (northern blotting) and proteins (western blotting). The transfer of protein patterns from a gel to a microporous membrane has been utilized universally to detect and characterize proteins, especially those of low abundance. Protein blotting has evolved greatly since its inception in 1979, as detailed in this work, allowing protein transfer to be accomplished in a variety of ways.

The acute clinical syndrome of toxic epidermal necrolysis (TEN) is currently thought to be a distinct clinical-pathological entity typically resulting from drug hypersensitivity. We describe an adult woman who experienced a fulminate pattern of apoptotic epidermal cell injury following tanning bed exposure while taking naproxen that resulted in a clinical presentation having combined features of drug-induced TEN and an infrequently recognized form of bullous cutaneous lupus erythematosus (LE). This case calls attention to the fact that TEN-like injury can occasionally be seen in settings other than drug hypersensitivity (e.g., LE, acute graft versus host disease) and illustrates the need for a unifying concept in this area. We therefore propose the term ‘Acute Syndrome of Apoptotic Pan-Epidermolysis (ASAP)’ to designate a clinical syndrome that is characterized by life-threatening acute and massive cleavage of the epidermis resulting from hyperacute apoptotic injury of the epidermis. We also review vesiculobullous skin disorders that can be encountered in LE patients and suggest a new classification scheme for such lesions.

Systemic lupus erythematosus and Sjögren syndrome remain elusive in the description of their underlying etiologic causes and pathogenic mechanisms. Although underlying genetic predisposition appears to contribute to both diseases based on twin and other genetic studies, additional factors must play a role. Over the decades additional factors, such as hormonal influence, UV light, environmental exposures (e.g., silica, solvents), and infectious agents have been postulated to play a role. Over the past few years additional information has been published concerning roles of various infectious agents in both lupus and Sjögren syndrome. Although the understanding of this field is still incomplete, significant advances are being made.

Antibodies binding components of the Ro/La (or SSA/SSB) ribonucleoprotein particle are found in the sera of patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) as well as mothers who give birth to babies with neonatal lupus. Anti-La occurs in a subset of sera that contain anti-Ro, and anti-La is found more commonly in sera of patients with SS than in sera from SLE patients. The fine specificity of autoantibodies binding 60 kDa has been studied extensively. Recent data have suggested that there are disease-specific epitopes which identify patients with either SLE or SS. Alternatively, other data suggest that the B cell epitopes of 60 kDa Ro vary according to the presence of anti-La. The present study was undertaken to determine whether binding of putative disease-specific 60 kDa Ro epitopes is associated with the diagnosis of SLE vs SS, or instead associated with the presence of anti-La. Anti-60 kDa Ro positive sera from 24 SLE patients and 44 SS patients were studied for antibodies binding two epitopes of 60 kDa Ro. We find the epitope defined by residues 171–190 is associated with anti-60 kDa Ro without anti-La, regardless of diagnosis. Meanwhile, binding of the epitope defined by residues 215–232 is not commonly found in anti-60 kDa Ro sera, especially in those sera with both anti-60 kDa Ro and anti-La. Thus, the fine specificity of antibody binding to 60 kDa Ro varies according to the presence of anti-La, not to the diagnosis of either SLE or SS.

Anti-Ro (or SSA) is found in the sera of patients with autoimmune rheumatic illnesses. All patients with anti-Ro defined by precipitation bind a 60 000 Da antigen (60 kDa Ro), whereas some patients also bind a 52 000 Da molecule (52 kDa Ro). In general, antibody binding is directed against native 60 kDa Ro and denatured 52 kDa Ro. The mechanism by which anti-52 kDa Ro arises in the setting of anti-60 kDa Ro is unknown. Conflicting data exist as to the existence of a physical interaction between the two proteins in cells and as to cross-reacting antibodies. Antibodies were affinity purified from a peptide within the leucine zipper region of 52 kDa Ro. These purified antibodies binding the 197-207 peptide from 52 kDa Ro (anti-52LZ) bound native 60 kDa Ro as well as denatured 52 kDa Ro. In addition, anti-52LZ also bound up to four regions from the sequence of 60 kDa Ro and a single conformational epitope of 60 kDa Ro. Thus, these primary sites represent components of the tertiary epitope. We hypothesized that if this was the case, these peptides making up a tertiary epitope would show molecular interaction. In fact, peptides from 60 kDa Ro have a molecular interaction with the 52 kDa Ro peptide as well as full-length 52 kDa Ro when assessed by surface plasmon resonance. The leucine-zipper region peptide from 52 kDa Ro bound three of the four peptides from 60 kDa Ro. These data suggest that these two molecular species, 60 and 52 kDa Ro, form a conformational epitope. This relationship may explain why anti-52 kDa Ro is found in association with anti-60 kDa Ro.

Protein protein interactions play a significant role in maintaining the structural and functional integrity of the cell. We used multiple antigen peptides (MAPs) to analyze such interactions within the Ro (or SSA) ribonucleoprotein complex. Our data showed that 60 kD Ro and La colocalize in the nucleus of the cell. Previous data have indicated that 60 kD Ro and La co-exist via interactions with the hYRNAs. We were interested to see whether 60 kD Ro and La interact with each other through protein protein interactions. MAPs were produced with sequences derived from the autoepitopes of 60 kD Ro. When used in agarose immunodiffusion certain MAPs formed precipitin lines specifically with Ro and La antigens. Used in affinity chromatography the Ro MAPs purified the Ro ribonucleoprotein particle from lymphocyte extract. Solid phase immunoassay and surface plasmon resonance (SPR) confirmed the observations obtained with agarose diffusion. Using SPR, kinetic analyses gave an apparent affinity constant of about 1 x 10(7) M(-1) for Ro-MAP-60 kD Ro interactions. The autoantigens Ro and La are specific targets in autoimmune diseases, particularly systemic lupus erythematosus (SLE) and Sjögren's syndrome, and are known to exist together as a complex with hYRNAs. The present data indicate that there are protein-protein interactions between Ro and La.

Residency training is inadequate with respect to the needs of general internal medicine doctors in several areas. We undertook this study to determine the practice habits and educational requirements of general versus subspecialty internists. A survey was mailed to 138 doctors who had completed at least a three-year university-based internal medicine post-graduate training. Sixty-three (46%) responded, of whom 32 completed additional training in a subspecialty of internal medicine. Many (14 of 32) subspecialists described their practice as general internal medicine (GIM) with a subspecialty emphasis. GIM was as important to their practice as it was to the general internists. General internists saw non-internal medicine disciplines as important but subspecialists did not. General internists frequently performed procedures that were not formally taught during training, while subspecialists rarely if ever performed a procedure outside the scope of their fellowship training. Internal medicine training programmes should be able to individualize training based on the career choices of trainees such that training will more fully prepare trainees for practice.

Efficient 5'-end labeling of DNA is an important procedure in recombinant DNA technology. Prior to labeling, it is important to inactivate alkaline phosphatase, used in the dephosphorylation of the DNA, by using proteinase K. Removal of proteinase K is usually performed by extracting twice with chloroform:isoamyl alcohol. In this report we show that extracting the sample four times with chloroform results in more efficient removal of sodium dodecyl sulfate (SDS), an important constituent of proteinase K buffer, which allows a 25- to 40-fold increase in labeling efficiency compared with extracting twice or once with chloroform, respectively. Unremoved SDS inhibits efficient labeling, possibly by inhibiting the activity of the kinase.

A gel filtration method was developed to estimate the number of conformational epitopes on the 60-kD Ro antigen. Anti-Ro Fab or Fab' was incubated with native Ro antigen at different ratios and the Stokes radius molecular weight of complexes was estimated by gel filtration. Binding was saturated at 9 to 11 Fab molecules per bovine Ro molecule. Two additional Fab or Fab' were bound if human Ro was used as the antigen. Isolated Ro antigen/anti-Ro Fab complexes were evaluated for the relative proportion of antigen to antibody at saturation of antigen with antibody and thus stoichiometry was determined. This provided data supporting there being between 7 and 11 binding sites, results similar to those with the gel filtration method. Experiments carried out with anti-Ro monoclonal antibodies showed one binding site per molecule of 60-kD Ro. Therefore, we have developed methods to count conformational epitopes on autoantigens and have applied it to the Ro/anti-Ro system. The data indicate that multiple conformational epitopes can be bound simultaneously by polyclonal anti-Ro sera from patients with systemic lupus erythematosus.

Spondyloarthropathies are closely related to genetics and certain bacteria. The ability to study these relationships at the molecular level has revealed increasing complexity in the interplay of genetics, microbes, and the diseases. Advances have been made in the genetics at the major histocompatibility complex. The mediators of inflammation in spondyloarthropathies have begun to be elucidated. The role of bacterial pathogenesis in the joints is being better defined and implies that viable organisms are in the joints of persons with reactive arthritis at some point in the illness. Disease-prone transgenic animals have been developed that demonstrate the need for an environmental trigger. The nature of the interaction of HLA-B27 with the microbes associated with the disease is unclear. Several hypotheses are being rigorously investigated.

Sacroiliac involvement is an early hallmark, but even so, patients with ankylosing spondylitis present a remarkable spectrum of disease. Research probing associations among spondylitis, enteric bacterial infection, and host expression of HLA-B27 may offer etiologic clues and point the way to disease-specific therapies.

Milk-alkali syndrome can be caused by ingesting large amounts of calcium carbonate. Coincident with the promotion of calcium carbonate as treatment for both dyspepsia and osteoporosis, milk-alkali syndrome is now a common cause of hypercalcemia severe enough to require admission to the hospital. The syndrome accounted for less than 2% of such admissions before 1990, but from 1990 through 1993, it was the cause of hypercalcemia for over 12% of these patients. Only primary hyperparathyroidism and hypercalcemia of malignancy (excluding multiple myeloma) are more common. The diagnosis of milk-alkali syndrome is made almost entirely based on the patient's history; careful attention to dietary practices and over-the-counter drug use is required, as numerous over-the-counter medications contain calcium carbonate. Modern assays for PTH demonstrate the expected suppression of PTH by hypercalcemia. Nonetheless, measurement of PTH must be performed in a timely manner as treatment with intravenous saline may result in hypocalcemia and elevated PTH soon after admission. Given the pathophysiology of milk-alkali syndrome compared to other causes of hypercalcemia, hypocalcemia with rebound hyperparathyroidism is probably unique to milk-alkali syndrome.

Objectives: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. Methods: Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. Results: In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient’s family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. Conclusion: The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′–5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi–Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ~8370 patients with SLE and ~7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case–control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25–2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E−13, OR=5.2, 95% CI=3.18–8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

Anti-Ro autoantibodies are frequently found in the sera of patients with Sjogren's syndrome, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus as well as in the sera of mothers of infants with the neonatal lupus syndrome. Close associations have been found between anti-Ro and a number of clinical manifestations, particularly including hematologic cytopenias, heart block, and photosensitive skin rashes. Serologic and genetic associations have been found between anti-Ro and anti-La, rheumatoid factor, hypergammaglobulinemia, the histocompatibility alleles DQ1 and DQ2, and alleles of the T-cell receptor beta chain gene. The origin of anti-Ro and other autoantigens is thought to relate to the etiology of Sjogren's syndrome and systemic lupus erythematosus and remains the most fundamental unanswered question preventing a comprehensive understanding of these diseases.

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.

Sir, We read with interest the review article entitled ‘Consequence of neo-antigenicity of the ‘altered self ’’ [1], where the authors discuss the importance of oxidation-specific protein adducts in plasma membranes. We would like to point out that we have also shown the importance of 4-hydroxynonenal (HNE), a lipid eroxidation by-product, modified Ro 60 (SS-A) autoantigen in the rapid development of autoimmunity in an animal model of SLE [2] and the role of oxidatively modified proteins in autoimmune diseases [3]. Ro 60 RNP is a common target of autoantibodies in both SLE and SS. This structure is made up of a 60 kDa protein non-covalently associated with at least one of four short uridine-rich RNAs (the hY RNAs) [3, 4]. These hY RNAs are also associated with the 48 000 molecular weight La (or SS-B) autoantigen. Anti-Ro is found in 25–40% of patients with SLE, while anti-La is found in substantially fewer patients [3, 4]. Tolerance against Ro 60 and other autoantigens was abrogated faster and strongly in the HNE-Ro 60-immunized animals compared with the Ro 60-immunuzed animals. Immunization with HNE-modified Ro 60 induced a rapid intramolecular epitope spreading (within the Ro 60 molecule) and a rapid inter-molecular epitope spreading to other autoantigens. Such a scenario envisages developing antibodies to 60 kDa Ro and thus autoimmunity to the entire Ro RNP particle after an initial immune response to oxidized Ro 60. We studied oxidative modification of Ro 60 since we and others observed free radical mediated peroxidative damage in SLE and other diseases [5–9]. Significantly higher HNE-modified protein levels have been found to occur in children with SLE [7]. Thus, we believe that oxidative modification of proteins is important in the generation of autoantibodies and thus brings about autoimmunity. Disclosure statement: The authors have declared no conflicts of interest.

Sjögren’s syndrome is a common autoimmune rheumatic disease. The most common symptoms of Sjögren’s syndrome are extreme tiredness, along with dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Saliva plays an essential role in numerous functions of the mouth. Xerostomia can be caused by medications, chronic diseases like Sjögren’s syndrome, and medical treatments, such as radiation therapy and bone marrow transplant. Xerostomia can eventually lead to difficulty in swallowing, severe and progressive tooth decay, or oral infections. Despite having excellent oral hygiene, individuals with Sjögren’s syndrome have elevated levels of dental caries, along with the loss of many teeth, early in the disease. Sjögren’s syndrome alters the protein profile and brings about a change in the composition of saliva. There is an increase in the levels of lactoferrin, β2-microglobulin, sodium, lysozyme C, and cystatin C, and a decrease in salivary amylase and carbonic anhydrase. Up to 90% of individuals with Sjögren’s syndrome have antibodies targeting the Ro 60 and La autoantigens. Natural aging, regardless of Sjögren’s syndrome, is also another factor that brings about a significant change in the composition of saliva. The most prevailing cause of xerostomia in elderly persons is the use of anticholinergic medications. Currently, there is no cure for Sjögren’s syndrome, and treatment is mainly palliative.

SUMMARY SLE is associated with the production of autoantibodies to self-constituents. In particular, certain ribonucleoprotein particles are targeted. Despite the multitude of autoantibodies produced and the remarkable concentrations of these antibodies in the sera of SLE patients, there have been little data that the autoantibodies found in SLE are involved in the pathogenesis of disease or its manifestations. The present work demonstrates that anti-Ro (or SSA) is associated with granulocytopenia, binds the surface of granulocytes and fixes complement to this membrane surface. Binding is a property of anti-Ro Fab fragments and can be inhibited by 60-kD Ro. However, the antigen bound on the surface of granulocytes is a 64 000 mol. wt protein that is a novel autoantigen in SLE. As suggested by inhibition studies, sequence identity between 60-kD Ro and eight tandem repeats in the 64-kD antigen may be responsible for the observed serologic cross-reactivity . These data imply that anti-Ro antibodies that also bind the 64-kD protein mediate neutropenia in patients with SLE.

In this space-age [1], rampant with high-flying advances in medicine and science many still find themselves enslaved to the vice of smoking, be it cigarettes, pipe, cigar, bidis or hookah. The adverse effects of smoking are well known [2–5]. There has been a surge in the use of hookah worldwide, contributed in part by the introduction of sweetened/flavoured tobacco and also by the misconception that the passage of smoke through water reduces its toxicity [3].

A pair of monozygotic twins with Sjögren's syndrome are described who both have large amounts of anti-Ro/SSA in their sera by ELISA, but no precipitin in double immunodiffusion. Unique among previously encountered specimens, sera from the twins inhibit the formation of Ro/SSA precipitins in double immunodiffusion by known anti-Ro/SSA positive SLE patients. The twins have near identical, clonally restricted anti-Ro/SSA autoantibodies as evaluated by isoelectric focusing and bind the same 60 kD Ro/SSA peptides. Thus, this pair of monozygotic twins has an identical fine specificity in their immune response to 60 kD Ro/SSA, despite potential differences in their immune response generated by random processes in the formation of immunoglobulin molecules and T cell receptors. These data imply that the anti-Ro/SSA found in these sera binds less than three epitopes such that soluble antigen/antibody complexes are formed instead of an insoluble complex that precipitates.

Autoimmune destruction and resultant failure of multiple organ systems constitute an uncommon entity known as type II polyglandular failure. Occasionally, the syndrome is familial, and in the kindreds studied, individual patients have manifested different sets of the associated diseases. We describe a large family in which the presence of HLA-DR4 was associated with development of this syndrome. More commonly, HLA-DR3 has been associated with type II polyglandular failure. The probands are monozygotic twin sisters in whom an identical set of autoimmune diseases occurred in the same order of onset and at approximately the same age. These data suggest that not only do specific factors predispose to this syndrome but also distinct factors determine which individual diseases are expressed.

Autoantibodies from many patients with systemic lupus erythematosus bind the Sm autoantigen B/B' polypeptide. The binding of serial serum specimens to the 233 overlapping octapeptides of Sm B/B' have shown that of the B/B'-derived octapeptides, PPPGMRPP and PPPGIRGP are early targets of the autoimmune response in some lupus patients. Rabbits immunized with PPPGMRPP and PPPGIRGP develop antibodies which not only bind these octapeptides, but also subsequently bind many other octapeptides of Sm B/B'. Eventually, the rabbits immunized with one octapeptide develop autoantibodies that bind other spliceosomal proteins including D, 70K, A, and C. Any mechanisms that operate to maintain tolerance or anergy for the spliceosome are thus overcome. Features considered typical of human systemic lupus erythematosus are also found in these peptide-immunized animals, such as antinuclear antibodies, anti-Sm precipitins, anti-double-stranded DNA, thrombocytopenia, seizures, and proteinuria. This disease model provides access to a mechanism for the development of humoral autoimmunity and may provide a basis to explain the immunopathogenesis of lupus in humans.

Autoantibodies binding the 70K nRNP polypeptide are commonly found in the serum of patients with systemic lupus erythematosus. IgG antibodies binding overlapping octapeptides of 70K nRNP have been evaluated in 10 patients with anti-nRNP precipitins, seven patients with other autoimmune serology, and four normal human sera. Neither normal controls nor patients without an anti-nRNP precipitin significantly bind any of the 70K nRNP octapeptides. Sera containing an anti-nRNP precipitin strongly bind various combinations of eleven different regions of the 70K nRNP protein. One antigenic region is consistently the most reactive in nine of ten nRNP precipitin positive sera tested. This sequence, KDKDRDRKRRSSRSR, is highly charged and has a similar pattern of alternating basic amino acids also present in seven of the other purported humoral autoimmune epitopes of the 70K nRNP polypeptide. The closely related DRKR and ERKR are important components of two of these epitopes. All regions of the 70K peptide bound by human anti-nRNP precipitin positive sera are very rich in the basic amino acids, especially lysine (chi-square = 23.03, odds ratio = 13.3, P < 0.000001).

Several human rheumatic diseases occur predominantly in persons who carry the histocompatibility (HLA) class I allele B27. They have also been related to Gram-negative enteric microorganisms. In addition, the recent recovery of peptides bound to B27 has allowed an understanding of the structural requirements for their binding. Using the accumulated data base of protein sequences, we have tested a series of hypotheses. First, we have asked whether the primary amino acid sequence of the hypervariable regions of HLA-B27 shares short sequences with the proteins of Gram-negative enteric bacteria. The data demonstrate that, unique among the HLA-B molecules, the hypervariable regions of HLA-B27 unexpectedly share short peptide sequences with proteins from these bacteria. Second, we have asked whether the enteric proteins tend to satisfy the structural requirements for peptide binding to B27 in those regions of the sequence shared with B27. This hypothesis also tends to be true, especially in an allelically variable part of the B27 sequence which is predicted to bind B27 if it were to be presented as a free peptide. We conclude that HLA-B27 and enteric Gram-negative bacteria have undergone a previously unappreciated form of convergent evolution which may be important in the process leading to these rheumatic diseases. Moreover, the regions of the enteric bacterial proteins which are contiguous with the short sequences shared with B27 tend to have structures which are also predicted to bind B27. These observations suggest a mechanism for autoimmunity and lead to the prediction that the B27-associated diseases are mediated by a subset of T-cell receptors, B27, and the peptides bound by B27.

Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of SLE patients have secondary Sjsgren9s syndrome. We undertook this study to determine whether autoimmune thyroid disease is associated with secondary Sjsgren9s syndrome in SLE. Families with more than one SLE patient were identified. All patients met the revised classification criteria, while SLE-unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjsgren9s syndrome was made on the basis of medical records review, interview, and questionnaire in the SLE patients and by questionnaire in the SLE-unaffected subjects. Of a total of 1138 SLE patients, 169 had Sjsgren9s syndrome. Fifty of these 169 (29.6%) also had autoimmune thyroid disease. Of the 939 SLE patients without Sjsgren9s syndrome, 119 (12.7%) had autoimmune thyroid disease (Π2 = 20.1, p