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This paper presents a model‐based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the precision medicine problem of identifying autoimmune disease patient subsets or classes who may require different treatments. We start with a family of restricted latent class models or RLCMs. However, in the motivating example and many others like it, the unknown number of classes and the definition of classes using binary states are among the targets of inference. We use a Bayesian approach to RLCMs in order to use informative prior assumptions on the number and definitions of latent classes to be consistent with scientific knowledge so that the posterior distribution tends to concentrate on smaller numbers of clusters and sparser binary patterns. The paper derives a posterior sampling algorithm based on Markov chain Monte Carlo with split‐merge updates to efficiently explore the space of clustering allocations. Through simulations under the assumed model and realistic deviations from it, we demonstrate greater interpretability of results and superior finite‐sample clustering performance for our method compared to common alternatives. The methods are illustrated with an analysis of protein data to detect clusters representing autoantibody classes among scleroderma patients. [ABSTRACT FROM AUTHOR]

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (Ts) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is strongly associated with autoantibodies against myeloperoxidase (MPO) and proteinase 3 (PR3). No clear consensus has been reached on the pathogenicity of these autoantibodies. Animal models for MPO-ANCA, in vitro data suggesting pathogenicity of ANCA, and one case of a neonate showing symptoms of vasculitis after transplacental transfer of MPO, argue in favour of a pathogenic role for ANCA. On the other hand, the presence of natural MPO and PR3 autoantibodies in healthy individuals, lack of a strong correlation between ANCA titres and disease activity, and the occurrence of ANCA-negative AAV patients argue against pathogenicity of ANCA. Recent papers have drawn attention to the possibility of epitope specificity defining ANCA pathogenicity. Certain MPO epitopes were found to be specific for active disease, and others remained present during remission or were also present in healthy individuals. One linear epitope, aa447–459, was not only exclusive for active disease, but also detected in the total Ig fraction of ANCA-negative patients, reactivity being masked in serum by ceruloplasmin. So, not all ANCA seems to be equal, some could be pathogenic while others are not. For development of an autoimmune response, a specific ANCA repertoire is required, which may occur through intra-molecular epitope spreading in patients. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment. [ABSTRACT FROM AUTHOR]

Previous studies have shown the down-regulating in vitro effect of cocoa flavonoids on lymphocyte and macrophage activation. In the present paper, we report the capacity of a long-term rich cocoa diet to modulate macrophage cytokine secretion and lymphocyte function in young rats. Weaned rats received natural cocoa (4% or 10% food intake), containing 32 mg flavonoids/g, for 3 weeks. Spleen immune function was then evaluated through the analysis of lymphocyte composition, their proliferative response and their ability to secrete cytokines and Ig. In addition, the status of activated peritoneal macrophages was established through tumour necrosis factor (TNF)-α secretion. The richest cocoa diet (10%) caused a reduction of TNF-α secretion by peritoneal macrophages showing anti-inflammatory activity. Similarly, although a 10% cocoa diet increased lymphocyte proliferation rate, it down-regulated T helper 2 (Th2)-related cytokines and decreased Ig secretion. These changes were accompanied by an increase in spleen B cell proportion and a decrease in Th cell percentage. In summary, these results demonstrate the functional activity of a cocoa-high dosage in down-regulating the immune response that might be beneficial in hypersensitivity and autoimmunity. [ABSTRACT FROM AUTHOR]

Peripheral blood mononuclear cells from patients with Sjögren's Syndrome spontaneously secrete autoantibodies to the La antigen when cultured in vitro. This paper reports that specific IgG autoantibody production in vitro is suppressed by pre-treatment of CD8+ enriched T cells with rabbit polyclonal antibodies to idiotypes borne by circulating autologous anti-La antibodies. Treatment of this T cell subpopulation with anti-idiotypes specific for circulating anti-La antibodies from other patients or for anti-DNA antibodies was without effect on anti-La antibody production. Similarly anti-La anti-idiotypes had no effect on the production of autoantibodies to other ribonucleoprotein antigens such as nRNP/Sm. These data show that CD8+ T cells are the main targets for anti-idiotypic control in vitro. We suggest that the relative deficit of these cells, plus a surfeit of CD4+ T cells at the site of the pathological lesion within the salivary gland permits localized production of autoantibodies. Thus, dysregulation of the idiotypic network could contribute to the pathogenesis of Sjögren's Syndrome. [ABSTRACT FROM AUTHOR]

Brain-reactive autoantibodies are thought to play an important role in mediating central nervous system (CNS) disorders in systemic lupus erythematosus (SLE), In this paper the developmental occurrence ofthese antibodies in the sera of autoimmune mice, i,e, NZB, NZB/W, MRL/I and BXSB mice were examined. All murine strains tested, whether autoimmune or not, showed some degree of serum reactivity toward brain antigens. Autoimmune mice, however, displayed higher levels of serum brain-reactive antibodies, and at earlier ages, than non-autoimmune mice. Immunofluorescence assays against brain sections and adsorption assays, with both neural and non-neural tissue, indicated a heterogeneity in the specificity of the populations of brain-reactive antibodies present. These studies provide an important step in characterizing the appearance and diversity of brain-reactive autoantibodies, with the goal of better understanding their significance and potential role in mediating CNS dysfunction in SLE. [ABSTRACT FROM AUTHOR]

Sent of some patients with systematic lupus erythematosus (SLE) contain IgG autoantibodies (F-&42sline;) which have been shown to stabilize the cell bound classical pathway C3 convertase of complement, C&42sline;. C&42sline; is susceptible to inactivation by the plasma protein C4bp while stabilized C&42sline; is relatively resistant to C4bp. The present study demonstrates that F-&42sline; by itself does not induce activation of the classical pathway in vitro but that it is able to modulate the immune complex-induced consumption of C2 and C3 in whole serum. Incubation of incremental concentrations of F-&42sline; with normal human serum (NHS) for 30 min at 30°C did not result in detectable consumption of Clq, C4, C2 and C3. However, when soluble immune aggregates or immune complexes were incubated in NHS together with 100 u/ml of F-&42sline;, a significant increase in consumption of C3 was seen as compared to the reaction mixture containing immune complexes or F-&42sline; alone. In addition the presence of F-&42sline; during the immune complex mediated consumption of complement was associated with relative protection of C2 consumption. (Fab)'2 and Fab' fragments of F-&42sline; behaved as intact F-&42sline;, except that their activities on a molar bask were less than that of intact F-&42sline;. The results presented in this paper suggest that F-&42sline; may play a regulatory role in the immune complex-mediated consumption at C2 and C3 in vivo. [ABSTRACT FROM AUTHOR]

In this paper we use a sensitive, 125I-anti-immunoglobulin-binding assay, recently adapted for use with tissue homogenates as targets, to demonstrate autoantibodies to brain, liver and heart in the sera of normal persons. Quantitative absorption analyses demonstrated that the autoantigens detected were in each case organ-specific, and the brain autoantigen was shown to be present In equal amounts on cerebral cortex, cerebral white matter and cerebellar cortex. The autoantibodies were shown to be IgM in nature by gel filtration studies and experiments where IgM was reduced to monomers, and were found to bind equally well at 4, 20 and 37 C. Cross-reactions with brain, liver and heart of rat and dog were unpredictable and usually weak. Parallel studies with kidney homogenates failed to detect anti-kidney autoantibodies, but immunofluorescence studies on frozen sections revealed large amounts of immunoglobulin in normal kidneys, mainly on glomerular and tubular basement membranes, raising the possibility that autoantibodies to kidney are present but that the autoantigen sites are saturated in vivo. Sera from patients with multiple sclerosis were indistinguishable from normal sera in their binding to brain homogenate, and CSF from five patients with multiple sclerosis did not bind at all to brain homogenate. The theoretical and practical significance of multiple IgM autoantibodies in normal persons, and the organ specificity of the autoantibodies, is discussed. [ABSTRACT FROM AUTHOR]

Summary: Dermatomyositis is a disease where skin and muscles become inflamed. Sometimes it affects just muscles, sometimes just the skin. Most patients fall within a spectrum where both are inflamed. Elevations of the enzyme creatinine kinase (CK) are found in the bloodstream if muscles are inflamed, and tests such as an electromyogram may also be abnormal. Dermatomyositis is an autoimmune condition, with antibodies directed against the patient's own tissues (autoantibodies). Different patterns of such autoantibodies are associated with different subsets of the condition. There is also an underlying cancer in a minority of adults with dermatomyositis. One group of autoantibodies is specifically associated with muscle inflammation. Within it is a family called anti‐TIF (transcriptional intermediary factor) antibodies, including anti‐TIF‐1α and ‐1γ antibodies. Anti‐TIF‐1α antibodies always appear with anti‐TIF‐1γ. In this paper from Japan, the authors investigate which conditions result when patients have a third autoantibody, anti‐TIF‐1β, on its own, without either of the other two. From 3442 stored serum (blood) samples from patients with connective tissue diseases, they found seven such patients. Six had dermatomyositis, but in two, muscles were either not involved (one patient) or involved but producing no symptoms (one patient); the other four patients had classic dermatomyositis but muscle involvement was mild and only one of the four had an elevated CK. One of these four patients did, however, have an underlying cancer. The seventh patient had 'undifferentiated connective tissue disease'. The authors conclude that anti‐TIF‐1β antibodies are associated with dermatomyositis where muscle inflammation is absent or only mild. Linked Article: Ueda‐Hayakawa et al. Br J Dermatol 2019; 180:881–887 [ABSTRACT FROM AUTHOR]

Presents an abstract of the research paper 'Clinical Features of Patients With and Without Autoantibodies in Chronic Idiopathic Urticaria: A Comparison,' by R.A. Sabroe, P.T. Seed, D.M. Francis, R.M. Barr, A. Kobza Black and M.W. Greaves presented at the Annual Meeting of the British Association of Dermatologists in Edinburgh, Scotland.