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Anti-membrane autoantibodies (MbA) have been reported in sera from patients with lupus nephritis (LN) but the targets of the MbA remain to be explored, which is the aim of the current study. Sera were collected from 40 patients with LN determined by renal biopsy, and from 30 systemic lupus erythematosus (SLE) patients without clinical evidence of LN. Thirty autoimmune disease control patients (rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis), and 30 healthy controls were also included. Using flow cytometry, the presence of anti-MbA was explored revealing that IgG anti-MbA positivity was associated with LN (62.5% vs 13.3%) when compared to non-LN SLE patients, autoimmune disease patients (6.7%) and healthy controls (0%). Next, using purified plasma membrane fractions from human embryonic kidney (HEK) cells, the more prominent targets and their occurrence rates were located at 50 kDa, 60/65 kDa, 90 kDa, 110 kDa, 180 kDa and 220 kDa. Alpha-actinin (110 kDa) autoAb was characterized as a major target in LN patients positive for anti-MbA, and anti-MbA binding activity was reduced (36.9 ± 13.7%) in the presence of α-actinin. Laminin (200 kDa) was also characterized as a minor target, which was not the case for annexin A2 (36 kDa). Finally, anti-MbA IgG subclass analysis indicated a predominance of IgG2. In conclusion, IgG anti-MbA were detected at high levels in LN patients supporting a primary pathogenic role for anti-MbA and anti-MbA/α-actinin+ in LN that needs further research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Toll-like receptors (TLRs) are positioned at the interface between innate and adaptive immunity. Unlike others, those such as TLR9, that recognize nucleic acids, are confined to the endosomal compartment and are scarce on the cell surface. Here, we present evidence for TLR9 expression on the plasma membrane of B cells. In contrast to endosomal TLR9, cell surface TLR9 does not bind CpG-B oligodeoxynucleotides. After B cell-receptor (BCR) stimulation, TLR9 was translocated into lipid rafts with the BCR, suggesting that it could serve as a co-receptor for BCR. Nevertheless, stimulation of B cells with anti-TLR9 antibodies did not modify the BCR-induced responses despite up-regulation of tyrosine phosphorylation of proteins. However, CpG-B activation of B cells, acting synergistically with BCR signals, was inhibited by anti-TLR9 stimulation. Induction of CD25 expression and proliferation of B cells were thus down-regulated by the engagement of cell surface TLR9. Overall, our results indicate that TLR9 expressed on the plasma membrane of B cells might be a negative regulator of endosomal TLR9, and could provide a novel control by which activation of autoreactive B cells is restrained., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Although B cell activating factor (BAFF) and its receptor BR3 are produced and expressed by many cells, their role has been restricted to the lymphocyte lineage. Using various techniques (RT-PCR, indirect immunofluorescence, flow cytometry analysis), we observed the expression of BR3 and the production of BAFF by the human salivary gland cell line, by epithelial cells from biopsies of Sjögren's syndrome patients and their controls, but also by salivary gland epithelial cells in culture. To decipher the role of BAFF and BR3 on epithelial cells, BAFF and BR3 were neutralized by blocking antibodies or RNA specific inhibitor (siBR3) and epithelial cell survival was analyzed. Blocking BR3 promotes epithelial cell apoptosis in vitro. This apoptosis resulted in the nuclear translocation of PKCδ. BAFF neutralization by various anti-BAFF antibodies leads to different effects depending on the antibody used suggesting that only some forms of BAFF are required for epithelial cell survival. Our study demonstrates that BR3 is involved in the survival of cultured epithelial cells due to an autocrine effect of BAFF. It also suggests that epithelial cells produce different forms of BAFF and that only some of them are responsible for this effect., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The B-cell activating factor belonging to the tumor-necrosis factor family BAFF contributes to autoimmune disorders. As such, BAFF might become a therapeutic target. However, this molecule has pleiotropic effects that are as numerous as they are varied. The real effect of each form (spliced, glycosylated, membrane bound, soluble, homotrimerized, heterotrimerized, multimerized) has not been well characterized yet. Consequently, conflicting results, regarding the serum concentrations of BAFF or its functional effect, exist in literature. BAFF quantification based on ELISA commercial kits was indeed found to be inaccurate. The complexity of the various forms of BAFF will be reviewed by focusing on the different structural aspects of the molecule. These data have particular implications for autoimmunity, not only because of the role of these factors on B cell growth and survival, but also their influence on the onset and severity of several autoimmune diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP). A key question that has emerged from these two characteristic features of SLE is whether the two processes are linked. New data provide support for such a link. For example, there is evidence that hypomethylated DNA is immunogenic, that anti-histone auto-Abs in patients with SLE bind epigenetic-sensitive hot spots and that epigenetically-modified RNP-derived peptides can modulate lupus disease. All in all, the available evidence indicates that a better understanding of dysregulation in epigenetics in SLE may offer opportunities to develop new biomarkers and novel therapeutic strategies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into follicular pathway when antigenic stimulation is combined with T cell signals. Here, we wished to identify stimuli contributing to the development into marginal zone B cells known to be involved in autoimmune response. We found that TLR9 stimulation of transitional B cells induces proliferation and specific maturation into CD24(-) CD38(+) CD21(high) CD23(low) IgM(high) IgD(low) and Notch2(high) B cells characteristics of marginal zone B cells. Terminal differentiation into antibody-secreting cell associated with isotype switch commitment is also triggered which leads to a striking production of autoantibodies. Interestingly, mature B cells do not differentiate into marginal zone pathway following TLR9 stimulation, nor do transitional B cells under antigenic and T cell combined signals. These results suggest that transitional B cells are specifically sensitive to TLR9 stimulation to produce autoreactive marginal zone B cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/purpose: Primary Sjögren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS., Methods: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed., Results: Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status., Conclusions: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Be they follicular cells within the germinal centers (GCs) or marginal zone (MZ), all naïve mature B lymphocytes need tonic signaling to stay alive. We reasoned that the same holds true for those B lymphocytes that proliferate in the salivary glands (SGs) of patients with primary Sjögren's syndrome. Based on B cell infiltration, 11 SGs and three tonsil samples were selected for further examination. Tissue sections were stained using CD20 combined with CD10, CD21, CD27, CD38 or IgD. They were also laser-microdissected for quantitative RT-PCR of transcription factors, GC-specific activation-induced cytidine deaminase (AID) and TLR9. Some B cell aggregates proved to be real GCs according to their membrane markers, whereas others were clusters of transitional type II B cells. These contained mRNAs for Notch-2 and Blimp-1, but not for Pax-5, Bcl-6 and AID. Unanticipated was the finding of mRNAs for TLR9 in these clusters of MZ B-cells, but not in the real GCs. Not only do TLR9 deliver sufficiency of tonic signaling to keep B cells alive, but they also confer autoreactive B cells with an MZ-like phenotype. Thus, TLRs might be targets for forthcoming biotherapies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

One way for intravenous Ig (IVIg) to affect responses of the B cells might be to operate through their TLR7 and TLR9. We confirm the ability of TLR agonists to induce CD25 expression in B cells. For this to occur, sialylated Fc-gamma of IgG included in the IVIg preparation are required. As a result, IVIg suppresses TLR-induced production of the proinflammatory IL-6, but not that of the anti-inflammatory IL-10. That is, IVIg mimics the effects of the MyD88 inhibitor. Finally, as we previously showed that IVIg induces CD22 to recruit the inhibitory SHP-1, we established that this enzyme was also involved in IVIg-induced inhibition of TLR9 signaling. This is the first report to demonstrate such a mechanism underlying the negative impact of IVIg on B lymphocytes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Regulatory functions for B lymphocytes have been reported in murine models of autoimmune diseases in which B-cell deficient mice were shown to exhibit exacerbated disease. The B cells responsible for the immune regulations were identified as a subpopulation of interleukin 10-secreting cells. However, the mechanism of induction and the characteristics of regulatory B cells in humans have been hardly studied. This study reports that regulation of T cell responses can be induced by B cells following CD40-dependent cognate interaction. T cell proliferation and cytokine production were differentially regulated. Thus, CD40-induced regulatory B cells partially inhibited T cell proliferation following CD40 interaction without requirement of soluble factor. In contrast, modulation of Th1 differentiation resulted from CD80- and CD86-dependent interactions and from IL-10 production. The suppressive effects were mediated by CD19(high)IgD+CD38(high)CD24(high)CD5(high) B cells and appeared to be indirect, through the induction of regulatory T cells as indicated by the appearance of Foxp3+CD4+CD25+T cells. These data suggest that activation signals from T cells initiate regulatory properties in B cells that modulate T cell responses involving regulatory T cells. Finally, studies in autoimmune patients revealed that regulation of T cell proliferation was defective in systemic lupus erythematosus but efficient in other diseases. Restoration of efficient B-cell regulatory activity could provide innovative B-cell based treatment of autoimmune diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

CD6 is one of a pair of related genes encoding CD5-associated receptors on all T cells and a subset of B cells. The current availability of "T1h", a humanized anti-CD6 monoclonal antibody for B cell-mediated autoimmune disorders revives analysis of the B-cell subset expression of CD6, particularly in primary Sjögren's syndrome (SS). Refined phenotype of B-lymphocytes peripheral blood (PB), bone marrow and tonsils revealed that the overlap between the expression of CD6 is less close to that of CD5 than currently acknowledged. In contrast to CD5, CD6 is absent on transitional B cells, while present on mature and memory B cells. Interestingly, the PB proportion of CD6(+) B cells is decreased in patients with primary SS, as opposed to those with rheumatoid arthritis. The reduction in primary SS does not result from the shedding of CD6 from the membrane of B cells, but from the lowering of memory B lymphocytes. It may result from the ability of CD6 to make transmigration of CD27(+) memory B cells into the salivary glands (SGs) easier. Consistent with this view is our finding that CD166 (one of the ligands for CD6) is highly expressed on epithelial cells of patients' SGs. This study is relevant in that the humanized T1h anti-CD6 becomes an alternative to anti-CD20 for treatment of primary SS., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

There is a crucial need for reliable diagnostic criteria for SS. Our objective was to evaluate the frequency of xerosis in patients with primary Sjögren's syndrome (SS), and compare histopathology of cutaneous sweat glands and labial salivary glands (LSGs), with respect to their contribution to the diagnosis. Twenty-two patients with primary SS and 22 matched normal volunteers were invited to rate their skin dryness on a visual analog scale. The skin was dryer (58.3 ± 10.1 versus 38.9 ± 7.6, P < 0.01), and xerosis more frequent (9 of 22 versus 2 of 22, P < 0.02) in the patients than in the controls. The axilla skin was chosen for a 6-mm punch biopsy. Lymphocytic infiltration was seen in the skin of 8 of the 12 patients tested. Two of them had normal LSGs. Most interestingly, B cell infiltrates were identified in patients' skin infiltrates, so that their presence might be a clue to the diagnosis of primary SS. These cell aggregates associated memory CD10-/CD20+/CD27+/IgD- B lymphocytes and immature CD20+/CD24 + lymphocytes. These latter findings strongly suggest that skin biopsies warrant inclusion into the routine clinical care of patients suspected of suffering from primary SS., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by a distinctive pattern of bone and joint destruction. RA patients have an increased risk of death. The incidence and prevalence of RA vary across populations, statistical methods, and disease definitions. In North America and Northern Europe, the incidence of RA is estimated at 20-50 cases per 100,000 population and the prevalence at 0.5-1.1%. Lower incidences and prevalences have been reported in Southern Europe, and few data are available for developing countries. Some studies showed declining incidences and prevalences after the 1960s. RA is a multifactorial disease that results from interactions between genetic and environmental factors. The main genetic factors are HLA-DRB1 and the tyrosine-phosphatase gene PTPN22. Among environmental factors implicated in the development of RA, smoking shows the strongest association with RA susceptibility and is also linked to worse outcomes. The aim of this review is to discuss the available data on the incidence and prevalence of RA, as well as the genetic and environmental risk factors associated with RA.

Autoimmune disease (AD) affects approximately 3% of the population. This is an enormous number, but ironically the study of autoimmunity has not taken on the significance of many other diseases because so many of the ADs are relatively uncommon. Indeed, despite enormous advances in the diagnosis and the treatment of AD, there is still a paucity of data on the etiological events that lead to the clinical pathology. For most other human diseases, the etiology is addressed and often solved by the use of epidemiology. Epidemiology consists of the study of prevalence of a disease, coupled with analysis of genetic factors and detection of environmental agents. In the context of autoimmune conditions, preclinical epidemiology has recently been favored, as a consequence of the discovery that autoantibody precedes overt disease. The idea of a North-South gradient in the prevalence of ADs, with a reciprocal gradient in that of infectious injuries has proven to be debatable. More importantly, environmentally-induced changes have been shown to modify certain diseases giving rise to the key concept of epigenetics. However, it is clear that major voids exist. Some of these voids were hoped to be solved by the use of genome-wide associations. This, however, has proven very problematic, as the genetic basis of AD is considerably more complicated than once believed. We now base our hopes on next generational sequencing as a brut force undertaking to partially decipher the genetic code that predisposes individuals to AD. This volume is a compilation of papers in Autoimmunity Reviews and the Journal of Autoimmunity and presented as part of the 7th International Congress on Autoimmunity in Ljubljana, Slovenia. It is clearly impossible to present data on the geoepidemiology of all of the AD. Instead, we attempted to generate interest amongst immunologists to generate papers that are thought provoking but also contemporary reviews., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Advances in genetics, such as sequencing of the human genome, have contributed to identification of susceptible genetic patterns in autoimmune diseases (AID). However, genetics is only one aspect of the diseases that does not reflect the influence of environment, sex or aging. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development, showing differences between AID patients and healthy controls but also showing how one disease differs from another. With regards to epigenetic abnormalities, DNA methylation and histone modifications could be affected leading to large spatial and temporal changes in gene regulation. Other epigenetic processes, such as the influence of the ionic milieu around chromatin and DNA supercoiling stresses may be suspected also. The newly described role of microRNAs in control of gene expression is important by promoting or suppressing autoreactivity in AID. As a consequence control of cellular processes is affected becoming conducive, for example, to the development of autoreactive lymphocytes in systemic lupus erythematosus, synoviocyte proliferation in rheumatoid arthritis, or neural demyelination in multiple sclerosis. Application of epigenetics to AID is in its infancy and requires new hypotheses, techniques, tools, and collaborations between basic epigenetic researchers and autoimmune researchers in order to improve our comprehension of AID. From this will arise new therapeutics, means for early intervention, and perhaps prevention., (Copyright 2009 Elsevier Ltd. All rights reserved.)

As a model to dissect the effects of CpG-oligonucleotides (CpG) on rituximab (RTX)-mediated therapeutic killing of autoimmune or malignant B lymphocytes, nude mice were grafted with Daudi human B cells. These mice were then injected with RTX alone or together with CpG. The human B cell aggregate was measured, and the reactive infiltrate analyzed after selective depletion of murine circulating cells. Macrophages (MØ) were identified in infiltrates, but not polymorphonuclear neutrophils (PMN), as confirmed by the failure of quantitative polymerase chain reaction to detect transcripts for PMN-specific myeloperoxidase in graft extracts. Evidence that MØ predominate over PMN in the anti-B cell RTX-induced immune mechanisms, include the presence of MØ-derived cytokines, and the lack of consequences of depletion of NK cells or B lymphocytes on the CpG-mediated effects on RTX. Interestingly however, removal of circulating PMN reduced the number of MØ attracted by the Daudi B cells. Our interpretation that CpG-induced complement activation is required for PMN to influence MØ was first based on overproduction of C5a in treated mice. This excess was due to the binding of the inhibitor of the alternative pathway of complement to CpG, as demonstrated by the elution of factor H from CpG-affinity-chromatography columns. Thus MØ are recruited to the tissue in the presence of C5a, and exploited locally by RTX., (Copyright 2009 Elsevier Ltd. All rights reserved.)

In primary biliary cirrhosis (PBC) serum markers other than anti-mitochondrial antibodies (AMA) are promising in terms of disease severity and comorbidities, as well represented by anti-nuclear antibodies (ANA). The aim of the present study was thus to evaluate the prevalence and clinical significance of a large profile of serum autoantibodies in PBC sera. We utilized 69 sera from European patients with PBC (including 20 AMA-negative) and 297 sera from geographically and sex-matched healthy controls. All sera were tested for the presence of ANA and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal disease. Autoantibodies other than AMA were detected in 53/69 (76%) PBC sera vs. 105/297 (35%) among controls. The prevalence of ANA (targeting dsDNA, Sm, chromatin, ribosomal-P, RNP, SmRNP, SSA, SSB, and centromere) and thrombophilia-associated autoantibodies (i.e. anti-beta2GPI, phosphatydilserine, prothrombin) was common among patients with PBC. When clinical features were compared, the presence of anti-prothrombin IgM was associated with a worse prognosis as represented by a higher Mayo score. We demonstrate an increased prevalence of ANA and thrombophilia-associated autoantibodies in PBC sera and an association between the latter autoantibodies and PBC stage. The role of thrombophilia-associated antibodies will warrant further studies, based in particular on the incidence of portal hypertension at early stages of PBC., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Interleukin (IL)-6 is a prevailing factor of polyclonal B-cell activation of B cells, and thereby of their tolerance breach. Its receptor (R) complex consists of a transducing unit, and a membrane-bound or soluble protein. Many activities ascribed to this cytokine are generated by the soluble IL-6R. Evidence has however been gleaned in autoimmune diseases that the system is instrumental in rheumatoid arthritis (RA), Sjögren's syndrome and systemic lupus erythematosus (SLE). To gain insight into the understanding of the mechanisms behind these observations, a prime example is the recombination-activating gene (Rag) machinery in B lymphocytes. It is interesting that the expression of Rags is favored by IL-6, and repressed by anti-IL-6R antibody (Ab) in RA and SLE. Not surprisingly, clinical benefits are reported in the treatment of autoimmune disorders with anti-IL-6R Ab, and other perspectives about to be open in biotherapy.

Given the prominent role currently assigned to B lymphocytes in systemic lupus erythematosus, it is not surprising that the B cell activity factor belonging to the tumor necrosis factor family (BAFF) is involved in its pathogenesis. This cytokine is produced in excess, and inserted into its receptors on the surface of circulating B cells. Up-regulation of BAFF is most likely to lead to breach of tolerance by aberrant survival of B cells directed to the self. Trials aimed at blocking BAFF have thus been set out. Yet the results are awaited.

The interest for B cells has recently been revived. They normally play a role in the development, the regulation, as well as the activation of lymphoid architecture: they regulate dendritic cells and T-cell subsets function through cytokine production. Receptor editing is also essential in B cells and aids in preventing autoimmunity. Both abnormalities in the distribution of B-cell subsets and clinical benefit response to B-cell depletion in autoimmune states illustrate their importance. A new area has thus been reached, whereby B lymphocytes return as a significant contributor to autoimmune disorders.

Using a simple but novel ELISA, we have screened 40 serum samples from patients with primary Sjögren's syndrome and 34 normal controls for IgG glycosylation deficiencies, identified by their specific ricin binding. Elevated levels of asialylated IgG were detected in 24 patients. The extent of asialylation was significantly higher in the patients with extraglandular manifestations than in the others. Interestingly, the correlation of asialylated IgG was apparent only with Raynaud's phenomenon and arthritis, and not other extraglandular manifestations. Strong correlations (P less than 0.01) were noted between asialylated IgG and rheumatoid factor or IgA-containing immune complexes.

IgA-, IgM- and IgG-containing immune complexes (CIC) were detected in 48, 19 and 12% of 52 patients with primary Sjögren's syndrome (SS), in 36, 38 and 56% of 45 patients with rheumatoid arthritis, and in 8, 5 and 3% of 40 normal controls. A high proportion of primary SS patients also had considerable amounts of serum IgA and elevated levels of IgA with rheumatoid factor (RF) activity. IgA-CIC and IgA-RF were more frequent (P less than 0.03 and less than 0.001) in the 27 primary SS patients with, than in the 25 without extraglandular manifestations. IgA-CIC could play a role in mediating the tissue injury associated with primary SS.

Cord blood B cells were immortalized in vitro with Epstein-Barr virus (EBV). Supernatants containing greater than 500 ng/ml IgM from clones/lines were tested for expression of anti-DNA-associated 16/6 and PR4 idiotypes (id) by ELISA. Four of 70 lines, but no clones, were positive for 16/6 id and none expressed the PR4 id. The presence of 16/6 id on four cell lines was associated with specificity for ssDNA, cardiolipin and Fc of IgG. No association was seen with binding to the K30 polysaccharide of Klebsiella. One clone binding this antigen also had anti-ssDNA, anti-Fc and anti-cardiolipin activity but did not express 16/6 id. Our data support the germ-line nature of the 16/6 id and are consistent with the notion that IgM autoantibody-producing B cells use VH genes which are part of the normal B cell repertoire.

A subset of B cells expressing the CD5 marker, a 67 KD molecule, has been implicated in the pathogenesis of autoimmune disease. To study the immunoglobulin repertoire of CD5+ B cells we investigated chronic lymphocytic leukemic (CLL) cells, since the majority of the malignant clones express CD5. CLL were induced to secrete their IgM in vitro by phorbol 12-myristate 13-acetate (PMA) and the supernatants screened for binding to a panel of autoantigens. Twelve out of 14 CLL clones were autoreactive, binding to Fc of IgG, ssDNA, dsDNA, histones, cardiolipin, or cytoskeletal components. Many also bound to more than one antigen tested for, showing multispecificity. Our data suggest that a high proportion of CD5+ B cells are programmed to secrete multispecific autoantibodies.

CD5, the human counterpart of Ly-1 molecules in the mouse, are detectable but weakly expressed on a minute fraction of circulating B cells. The number of CD5 + B cells in the blood of patients with Sjögren's syndrome was slightly higher than in control blood, but it became statistically significant after treatment of the cells with phorbol myristic acetate. These numbers were even higher in patients with homogeneous serum bands than in the others. A few scattered cells were stained with anti-human IgM antibody on salivary gland sections, and among them 5-10% were found to be positive for anti-CD5.