The Mst1 Kinase Is Required for Follicular B Cell Homing and B-1 B Cell Development

The Mst1 and 2 cytosolic serine/threonine protein kinases are the mammalian orthologs of the Drosophila Hippo protein. Mst1 has been shown previously to participate in T-cell and B-cell trafficking and the migration of lymphocytes into secondary lymphoid organs in a cell intrinsic manner. We show here that the absence of Mst1 alone only modestly impacts B cell homing to lymph nodes. The absence of both Mst1 and 2 in hematopoietic cells results in relatively normal B cell development in the bone marrow and does not impact migration of immature B cells to the spleen. However, follicular B cells lacking both Mst1 and Mst2 mature in the splenic white pulp but are unable to recirculate to lymph nodes or to the bone marrow. These cells also cannot traffic efficiently to the splenic red pulp. The inability of late transitional and follicular B cells lacking Mst 1 and 2 to migrate to the red pulp explains their failure to differentiate into marginal zone B cell precursors and marginal zone B cells. Mst1 and Mst2 are therefore required for follicular B cells to acquire the ability to recirculate and also to migrate to the splenic red pulp in order to generate marginal zone B cells. In addition B-1 a B cell development is defective in the absence of Mst1

A role for apoptosis-inducing factor in T cell development

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report that aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell-autonomous thymocyte developmental block associated with apoptosis at the β-selection stage, independent of T cell receptor β recombination. No abnormalities are observed in the B cell lineage. Transgenes encoding wild-type or DNA-binding–deficient mutant Aif rectify the thymic defect, but a transgene encoding oxidoreductase activity–deficient mutant Aif does not. The Hq thymic block is reversed in vivo by antioxidant treatment, and Hq T but not B lineage cells show enhanced oxidative stress. Thus, Aif, a ubiquitous protein, serves a lineage-specific nonredundant antiapoptotic role in the T cell lineage by regulating reactive oxygen species during thymic β-selection

Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα.

Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-κB α (IκBα) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling. Lymphotoxin β receptor (LTβR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-κB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IκBα mutant → Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IκBα deficiency and suggests that correction of this niche is critical for reconstituting their immune function

Clonally expanded cytotoxic CD4+ T cells and the pathogenesis of IgG4-related disease

IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions, with dense lymphoplasmacytic infiltrates containing a preponderance of IgG4-expressing plasma cells. CD4+ T cells and B cells constitute the major inflammatory cell populations in IgG4-RD lesions. IgG4-RD patients with active, untreated disease show a marked expansion of plasmablasts in the circulation. Although the therapeutic depletion of B cells suggests a role for these cells in the disease, a direct role for B cells or IgG4 in the pathogenesis of IgG4-RD is yet to be demonstrated. Among the CD4+ T-cell subsets, Th2 cells were initially thought to contribute to IgG4-RD pathogenesis, but many previous studies were confounded by the concomitant history of allergic diseases in the patients studied and the failure to use multi-color staining to definitively identify T-cell subsets in tissue samples. More recently, using an unbiased approach to characterize CD4+ T-cell subsets in patients with IgG4-RD – based on their clonal expansion and ability to infiltrate affected tissue sites – CD4+ CTLs have been identified as the major CD4+ T-cell subset in disease lesions as well as in the circulation. CD4+ CTLs in affected tissues secrete pro-fibrotic cytokines including IL-1β, TGF-β1, and IFN-γ as well as cytolytic molecules such as perforin and granzymes A and B. In this review, we examine possible mechanisms by which activated B cells and plasmablasts may collaborate with the expanded CD4+ CTLs in driving the fibrotic pathology of the disease and describe the lacunae in the field and in our understanding of IgG4-RD pathogenesis

Striking Immune Phenotypes in Gene-Targeted Mice Are Driven by a Copy-Number Variant Originating from a Commercially Available C57BL/6 Strain

We describe a homozygous copy-number variant that disrupts the function of Dock2 in a commercially available C57BL/6 mouse strain that is widely used for backcrossing. This Dock2 allele was presumed to have spontaneously arisen in a colony of Irf5 knockout mice. We discovered that this allele has actually been inadvertently backcrossed into multiple mutant mouse lines, including two engineered to be deficient in Siae and Cmah. This particular commercially obtained subline of C57BL/6 mice also exhibits several striking immune phenotypes that have been previously described in the context of Dock2 deficiency. Inadvertent backcrossing of a number of gene-targeted mice into this background has complicated the interpretation of several immunological studies. In light of these findings, published studies involving immune or hematopoietic phenotypes in which these C57BL/6 mice have been used as controls, as experimental animals, or for backcrossing will need to be reinterpreted

Comparison of hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients

 Abstract Backgrounds: Thyroid hormones play an important physiological role in human metabolism. Erythrocyte abnormalities are frequently associated with thyroid disorder. However, they are rarely investigated and related to the subclinical and primary hypothyroidism in Kashmiri Patients. In this study an attempt was made to study hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients. Methods: This retrospective study included 600 subjects, among which were untreated subclinical hypothyroid (n=110), treated subclinical hypothyroid (n=110), untreated primary hypothyroid (n=100), treated primary hypothyroid (n=100) and euthyroid (n=180). This study was carried out at Department of Biochemistry, Government Medical College Srinagar. The hematological parameters and thyroid profile of the subjects were assessed by the Sysmex (Italy) and ECLIA (Germany) 2010 automatic analyzer. Mean, standard deviation (SD), analysis of variance (Two-way ANOVA), and multiple comparisons were used to report our results, with p<0.05 or p<0.01 considered as statistically significant. Results: In this study group we compared the hematological parameters in these groups, untreated subclinical hypothyroid, treated subclinical hypothyroid, untreated primary hypothyroid, treated primary hypothyroid and euthyroid. We found that hematological parameters like Hb, RBC, MCV, HCT, RDW,RBC% were significantly increased in untreated subclinical hypothyroidism and untreated primary hypothyroidsm, with the p value being less than 0.05 whereas, in treated SCH & Pr. Hypothyroid, results were insignificant. The results reported in these groups as mean±SD, were statistically tested by ANOVA and multiple comparison tests. In untreated subclinical hypothyroid the values were: Hb (10.83±1.33 g/dl ), RBC (4.21±0.66 106/μl), MCV (84.56±6.84 fL), HCT (38.5±2.2 %), RDW (17.91±2.37 fL), RBC% (84.36±13.2 %) and in untreated primary hypothyroid, Hb (10.73±0.86 g/dl), RBC (4.63±0.51 106/μl), MCV (83.34±6.92 fL), HCT (38.6±2.6%), RDW (14.93±5.47 fL), RBC% (92.63±10.30%) suggesting that these patients were at risk of anemia and other erythrocyte abnormalities. MCV is an inexpensive approach to study the types of anemia and explore related information like production, destruction, loss and morphological changes of RBC'S. Conclusion: The thyroid dysfunction is frequently associated with anemia in subclinical hypothyroidism and primary hypothyroidism. Subclinical hypothyroidism (SCH) is associated with serious complications. Substantial numbers of patients with the risk of SCH could be getting converted into primary hypothyroidism. Such conditions should be identified and corrected. On the other hand, their presence could move to a thyroid dysfunction, allowing its early management.&nbsp