Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.     

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.     

Beyond the joints,the extra-articular manifestations in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory disease typically affecting the joints, but the systemic inflammatory process may involve other tissues and organs. Many extra-articular manifestations are recognized, which are related to worse long outcomes. Rheumatoid nodules are the most common extra-articular feature, found in about 30% of patients. Secondary Sjögren's syndrome and pulmonary manifestations are observed in almost 10% of patients, also in the early disease. Active RA with high disease activity has been associated with an increased risk of such features. Male gender, smoking habit, severe joint disease, worse function, high pro-inflammatory markers levels, high titer of rheumatoid factor, and HLA-related shared epitope have been reported as clinical predictors of occurrence of these rheumatoid complications. In addition, there is a little evidence deriving from randomized controlled trials in this field, thus the therapeutic strategy is mainly empiric and based on small case series and retrospective studies. However, considering that these extra-articular manifestations are usually related to the more active and severe RA, an aggressive therapeutic strategy is usually employed in view of the poor outcomes of these patients.The extra-articular features of RA remain, despite the improvement of joint damage, a major diagnostic and therapeutic challenge, since these are associated with a poor prognosis and need to be early recognized and promptly managed.     

Lanthanide complexes based on a new bis-chelating carbacylamidophosphate (CAPh) scorpionate-like ligand

The novel bis-chelating carbacylamidophosphate type ligand, tetramethyl[pyridine-2,6-diyldi(iminocarbonyl)]diamidophosphate (H₂L), and its sodium salt, NaHL, have been synthesized and their structural properties have been investigated. Coordination compounds of lanthanides [Ln(HL)₂NO₃]·i-PrOH (Ln = Eu³⁺, Tb³⁺) were obtained for the first time, isolated in the individual state and characterized by means of IR and NMR spectroscopies, electrospray ionization mass spectrometry (ESI-MS), potentiometric titration, and elemental, thermal gravimetric and X-ray diffraction analyses. It was shown that H₂L behaves like a scorpionate type ligand and in a mono-deprotonated form coordinates in a tridentate manner via the oxygen atoms of phosphoryl and carbonyl groups with formation of a mononuclear metal complex. The protonation constants of H₂L and stability constants of Eu³⁺ and Tb³⁺ complexes have been determined. According to the results of X-ray diffraction analysis the H₂L and [Ln(HL)₂NO₃]·i-PrOH molecules have monomeric structure but NaHL is a dimer. The Hirshfeld surface and fingerprint plots of the compounds have been used to analyze various hydrogen bonds and intermolecular interactions displayed in the crystal structure.

A new bis-chelating scorpionate type CAPh ligand and its lanthanide complexes in solid state and solution.     

Reproductive Immunology: a Focus on the Role of Female Sex Hormones and Other Gender-Related Factors

Reproductive immunology has attracted the attention of researchers interested in fertility and pregnancy as well as those interested in immunity and autoimmunity. Over the past couple of decades, a wealth of data on the immune-reproductive interactions has been generated. This issue of the Journal will examine several topics including the role of immune factors in the induction of anti-Ro antibody-mediated autoimmunity in neonates and the immunological effects of gender and sex hormones. The possible implications of the research reviewed here for the development of novel therapeutic approaches are also addressed.     

Prolactin as a modulator of B cell function: implications for SLE.

Prolactin is not only a lactigenic hormone but also an immunomodulator involved in lymphocyte survival, activation and proliferation. There is increasing data implicating prolactin in autoimmunity, and specifically in SLE. Increased serum prolactin levels have been reported in lupus patients of both genders, and have been associated with accelerated disease expression and early mortality in lupus-prone mice. Furthermore, suppression of prolactin secretion with bromocriptine provides beneficial effects in murine lupus, and perhaps in some SLE patients as well. Treatment with prolactin that causes mild to moderate hyperprolactinemia, similar to that present in SLE patients, breaks tolerance and induces a lupus-like illness in non-spontaneously autoimmune mice with a susceptible genetic background. These immuno stimulatory effects of prolactin are mediated by a decrease in negative selection and the maturation of autoreactive B cells to the follicular subset. Consistent with the fact that follicular B cells are T cell dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B cell tolerance. In mice, the effects of prolactin on the immune system are genetically determined, suggesting that only a subset of SLE patients are likely to have a prolactin-responsive disease. The manipulation of serum prolactin or, even more specifically, follicular B cells that are susceptible to the immuno stimulatory effects of prolactin, may provide novel therapeutic options for those SLE patients with a prolactin-modulated disease.     

Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer

Aim  

In the current study, we investigated the expression of TGF-β1, its receptor TGFβRII, and the signaling proteins Smad4 and Smad7 in colorectal cancer tissue in relation to infiltration with antigen-presenting cells and some clinical and pathologic parameters of disease progression in patients with colorectal cancer (CRC).     

Adult nemaline myopathy with trabecular muscle fibers

The term “trabecular myopathy” has been used to designate a syndrome resembling limb‐girdle muscular dystrophy in which the predominant pathological feature is an abundance of lobulated or trabecular muscle fibers. However, the validity of this nosological entity has not been verified. Herein we describe a 63‐year‐old man with a severe, progressive myopathy who exhibited the typical pathological features of both trabecular myopathy and nemaline myopathy in association with a biclonal gammopathy. In this case, adult‐onset nemaline myopathy was probably the primary disease process. The diagnostic significance of trabecular muscle fibers remains uncertain. Muscle Nerve, 2008