Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies.

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19+ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.

Systematic review of infliximab-induced autoantibodies and systemic lupus erythematosus.

The present systematic review aims to discuss infliximab-induced autoantibodies and subsequent onset of systemic lupus erythematosus (SLE) through the analyses of primary reports measuring autoantibodies both before and after the administration of infliximab for the treatment of several diseases - e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn's disease. Our literature search was performed in nine databases - PubMed, Science Direct, Scopus, Web of Knowledge, Scirus, Cochrane, EMBASE, Scielo and LILACS, and the search query retrieved 998 primary reports, from which 24 articles were selected and further narrowed down to 14, based on our inclusion criteria. Two independent reviewers performed the article selection and a third reviewer solved discrepancies. Our inclusion criteria comprised primary reports of phase IV clinical trials with duration of at least three months. In total, 760 patients were evaluated and the most prevalent assays performed in the studies were anti-nuclear antibodies (ANA), anti-double stranded DNA antibodies (anti-dsDNA), and antibodies to saline-extracted antigens (ENA panel). Of all patients evaluated, 10 (1.3%) showed clinical signs and laboratorial evidence of infliximabinduced SLE.

Revisão sistemática da indução de autoanticorpos e lúpus eritematoso pelo infliximabe / Systematic review of infliximab-induced autoantibodies and systemic lupus erythematosus

Nesta revisão sistemática abordamos a indução de autoanticorpos e lúpus eritematoso pelo infliximabe, analisando estudos que dosaram vários autoanticorpos antes e após o uso do infliximabe em diversas doenças (artrite reumatoide, espondilite anquilosante, artrite psoriásica e doença de Crohn). Nossa busca foi realizada em nove bases de dados (Pub-Med, ScienceDirect, Scopus, Web of Knowledge, Scirus, Cochrane, EMBASE, Scielo e LILACS). Foram encontradas 998 referências; 24 artigos foram separados na íntegra, dos quais 10 foram excluídos por não entrarem em nossos critérios de seleção. A escolha dos artigos foi realizada por dois revisores, e as divergências foram resolvidas por um terceiro revisor. Incluímos estudos de fase IV, com no mínimo três meses de duração. No total foram estudados 760 pacientes; o fator antinuclear, o anticorpo anti-DNA de dupla hélice e os antígenos extraídos pela salina foram os mais verificados. De todos os pacientes, apenas 10 (1,3%) apresentaram manifestações clínico-laboratoriais de lúpus induzido por infliximabe.

The present systematic review aims to discuss infliximab-induced autoantibodies and subsequent onset of systemic lupus erythematosus (SLE) through the analyses of primary reports measuring autoantibodies both before and after the administration of infliximab for the treatment of several diseases - e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn's disease. Our literature search was performed in nine databases - PubMed, Science Direct, Scopus, Web of Knowledge, Scirus, Cochrane, EMBASE, Scielo and LILACS, and the search query retrieved 998 primary reports, from which 24 articles were selected and further narrowed down to 14, based on our inclusion criteria. Two independent reviewers performed the article selection and a third reviewer solved discrepancies. Our inclusion criteria comprised primary reports of phase IV clinical trials with duration of at least three months. In total, 760 patients were evaluated and the most prevalent assays performed in the studies were anti-nuclear antibodies (ANA), anti-double stranded DNA antibodies (anti-dsDNA), and antibodies to saline-extracted antigens (ENA panel). Of all patients evaluated, 10 (1.3%) showed clinical signs and laboratorial evidence of infliximabinduced SLE.

Hormone replacement therapy increases levels of antibodies against heat shock protein 65 and certain species of oxidized low density lipoprotein.

Hormone replacement therapy (HRT) reduces cardiovascular risks, although the initiation of therapy may be associated with transient adverse ischemic and thrombotic events. Antibodies against heat shock protein (Hsp) and oxidized low density lipoprotein (LDL) have been found in atherosclerotic lesions and plasma of patients with coronary artery disease and may play an important role in the pathogenesis of atherosclerosis. The aim of the present study was to assess the effects of HRT on the immune response by measuring plasma levels of antibodies against Hsp 65 and LDL with a low and high degree of copper-mediated oxidative modification of 20 postmenopausal women before and 90 days after receiving orally 0.625 mg equine conjugate estrogen plus 2.5 mg medroxyprogesterone acetate per day. HRT significantly increased antibodies against Hsp 65 (0.316 +/- 0.03 vs 0.558 +/- 0.11) and against LDL with a low degree of oxidative modification (0.100 +/- 0.01 vs 0.217 +/- 0.02) (P<0.05 and P<0.001, respectively, ANOVA). The hormone-mediated immune response may trigger an inflammatory response within the vessel wall and potentially increase plaque burden. Whether or not this immune response is temporary or sustained and deleterious requires further investigation.

Slowly progressing type 1 diabetes: persistence of islet cell autoantibodies is related to glibenclamide treatment.

BACKGROUND: Several experimental studies in rats have demonstrated that sulfonylurea treatment increases autoantigen expression in B-cells. This phenomenon may be deleterious for the preservation of residual beta cell function in patients with slowly progressing type 1 diabetes or latent autoimmune diabetes of adult (LADA). AIM/HYPOTHESIS: The aim of the present study was to evaluate whether the exclusion of glibenclamide in the treatment of ICA positive type 2 diabetic patients may diminish or halt the humoral autoimmune response against B-cells as well as improve metabolic control and insulin secretion. SUBJECTS AND METHODS: Fourteen type 2 diabetic patients with pancreatic autoimmunity (ICA+ and GABA+) and treated with insulin and glibenclamide (duration of disease 2.0 +/- 2.2, range 0.1-7 years and age 53 +/- 12.5, range 36-75 years) were studied. Patients were randomly assigned to two treatment groups, Group 1: insulin monotherapy (n = 8, age 53 +/- 6.4 years) (Exclusion of glibenclamide) and, Group 2: insulin plus glibenclamide (n = 6, age 53.5 +/- 16.9) (Unmodified treatment). Both groups were investigated at the beginning of the study and after one year for the following parameters: ICA and anti-GAD65 antibodies, fasting glucose and fasting C-peptide. RESULTS: In group 1, six out of eight patients became ICA negative while all patients in group 2 remained ICA positive (p = 0.0097). Fasting glucose concentrations improved in group 1 (4.6 +/- 2.8) in relation to group 2 (11.5 +/- 5.5, p = 0.0023) after one year of treatment. No differences were found for anti-GAD antibodies and fasting C-Peptide between the groups. CONCLUSIONS: These data show that exclusion of glibenclamide in the treatment of ICA+ type 2 diabetic patients partially decreases specific autoimmunity against endocrine pancreatic cells and improves metabolic control. This may reflect decreased expression of B-cell autoantigens suggesting that insulin monotherapy is a better choice for the treatment of LADA.

Autoantibody production in healthy elderly people is not promoted by interleukin-10 although this cytokine is expressed in them by a peculiar CD8+CD3+ large granular cell subpopulation.

Healthy elderly people tend to have autoantibodies in their sera. These antibodies, not being associated with any clinical manifestation, have been considered as natural autoantibodies. In systemic lupus erythematosus, as well as in rheumatoid arthritis, the presence of autoantibodies characteristic of these disease (anti-dsDNA and rheumatoid factor, respectively) depends on the endogeneous production of IL-10. The same could hold true for autoantibodies found in healthy elderly individuals. In the present work, the authors analysed whether an increased production of IL-10 contributed to the production of autoantibodies in elderly people. The authors found that there is neither increased in vivo gene expression nor augmented production of IL-10 by peripheral blood mononuclear cells from elderly women even if they do produce autoantibodies. The authors further sought to determine if the production of autoantibodies is inhibited in vitro by adding an anti-IL-10 MoAb to cell cultures and found that it is not. Despite these negative findings of a role for IL-10 in the production of autoantibodies in elderly people, the authors investigated which cells produce IL-10. In so doing they found that intracellular IL-10 expression occurred exclusively in monocytes in young female controls, but in elderly females it involved also CD8+CD3+ large granular cells. These results indicate that autoantibody production in healthy aged individuals is IL-10 independent.

Voluntary intake of "Tiquira", an alcoholic beverage prepared from fermented manioc, decreases immunoglobulin production and increases self-reactivity in mice.

UNLABELLED: We studied the effects of chronic voluntary ingestion of "Tiquira" (50%)--an alcoholic beverage prepared from fermented manioc, widely consumed in Maranhão,--on the natural immunological activity of young adult (2-3 months old) C57B1/6J mice (16-17 g) by evaluating the number of plaque-forming cells (PFCs) in the spleen and by titrating serum antibodies by ELISA. Voluntary ingestion of "Tiquira" for 30 days decreased immunoglobulin secretion in serum ( CONTROL: 1600 +/- 30 vs EXPERIMENTAL: 193 +/- 20), caused an impressive reduction in the total number of PFCs in the spleen ( CONTROL: 482 +/- 22 vs EXPERIMENTAL: 58 +/- 3) and increased the proportion of self-reacting antibody molecules in serum ( CONTROL: 119 +/- 16 vs EXPERIMENTAL: 800 +/- 20) and self-reactive PFCs to mouse red blood cells (MRBC) in the spleen ( CONTROL: 183 +/- 14 vs EXPERIMENTAL: 272 +/- 16; N = 10 animals per group). These preliminary results suggest that the voluntary ingestion of "Tiquira" for 30 days may interfere with immunological relations by decreasing the total number of immunoglobulin secreting cells and increasing the anti-self antibody production. Experiments are in progress to determine if ethanol or other substances present in "Tiquira" are responsible for the effects documented here.