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Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR + microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3 + , CD4 + , and CD8 + T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.

B-1a cells produce "natural" antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the fundamental selection mechanisms that shape their polyreactive repertoires are poorly understood. Here, we identified a B cell progenitor subset defined by Fc receptor-like 6 (FCRL6) expression, harboring innate-like defense, migration, and differentiation properties conducive for natural Ab generation. Compared to FCRL6 - pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6 + progenitors, yielded V H repertoires with biased distal Ighv segment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Beyond nascent autoreactivity, V H 11 productivity, which predominates phosphatidylcholine-specific B-1a B cell receptors (BCRs), was higher for FCRL6 + cells as was pre-BCR formation, which was required for Myc induction and V H 11, but not V H 12, B-1a development. Thus, FCRL6 revealed unexpected heterogeneity in the developmental origins, regulation, and selection of natural Abs at the pre-BCR checkpoint with implications for autoimmunity and lymphoproliferative disorders., (Copyright © 2020 Honjo, Won, King, Ianov, Crossman, Easlick, Shakhmatov, Khass, Vale, Stephan, Li and Davis.)

Glioblastoma, also known as glioblastoma multi-forme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic re-programming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment., Competing Interests: Conflict of interest: The authors declare no conflict of financial interests.

Members of the extended Fc receptor-like (FCRL) family in humans and mice are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. Although the majority of these proteins repress B cell receptor-mediated activation, there is an emerging evidence for their bifunctionality and capacity to counter-regulate adaptive and innate signaling pathways. In light of these findings, the recent discovery of ligands for several of these molecules has begun to reveal exciting potential for them in normal lymphocyte biology and is launching a new phase of FCRL investigation. Importantly, these fundamental developments are also setting the stage for defining their altered roles in the pathogenesis of a growing number of immune-mediated diseases. Here we review recent advances in the FCRL field and highlight the significance of these intriguing receptors in normal and perturbed immunobiology.

Background: Serum calcitonin is the most useful tumor marker for the diagnosis and follow-up of medullary thyroid carcinoma (MTC). Spurious hypercalcitoninemia caused by heterophilic antibody interference (HAI) is rarely found in patients without MTC., Methods: We studied 2 patients with hypercalcitoninemia and thyroid nodules, but no evidence of MTC on fine-needle aspiration cytology. We performed calcium stimulation tests, measured serum calcitonin with another calcitonin kit, performed dilution tests, and remeasured serum calcitonin after applying heterophilic blocking tubes., Results: In a 31-year-old woman with no response to the calcium stimulation test, serum calcitonin was <5 pg/mL using another kit. After we applied heterophilic blocking tubes, the serum calcitonin level decreased to normal range. We concluded that patient had spurious hypercalcitoninemia. In a 63-year-old woman, all tests revealed that the patient had true hypercalcitoninemia. The patient underwent total thyroidectomy that revealed MTC., Conclusions: We suggest that patients suspected for spurious hypercalcitoninemia should undergo further investigation due to HAI.

Of a number of mAbs made by immunization with sort-purified marginal zone (MZ) B cells, one was shown to recognize the mouse scavenger receptor CD36. Although CD36 is expressed by most resting MZ B cells and not by follicular and B1 B cells, it is rapidly induced on follicular B cells in vitro following TLR and CD40 stimulation. In response to T-independent and T-dependent Ag challenge, we found that CD36 was expressed on IgM+ plasma cells, but down-regulated on isotype-switched plasma cells in vivo. Although development, localization, and phenotype of MZ B cells in CD36-/- mice appeared normal, there was a minor block in the transitional stages of mature B cell development. In both primary and secondary Ab responses to heat-killed Streptococcus pneumoniae (R36A strain), both phosphoryl choline (PC)-specific IgM and IgG levels in CD36-/- mice were slightly reduced compared with wild-type mice. In addition, mice deficient in both TLR2 and CD36 produced significantly reduced levels of anti-PC IgG titers than those of single gene-deficient mice, suggesting that they may cooperate in an anti-PC Ab response. Collectively, these results show that CD36 does not affect the development of B cells, but modulates both primary and secondary anti-PC Ab responses during S. pneumoniae infection similarly to TLR2.

Two members of the recently identified FcR homolog (FcRH) family in mice demonstrate preferential B cell expression. One of these, FcRH3, encodes a type I transmembrane protein with five extracellular Ig domains and a cytoplasmic tail with a consensus ITIM and a noncanonical ITAM. Analysis of full-length cDNAs from five different mouse strains defines two FcRH3 alleles. A panel of FcRH3-specific mAbs was generated to define its expression pattern and functional potential on B lineage cells. Although poorly detected on the majority of bone marrow or peripheral blood cells, FcRH3 was readily identified on splenic marginal zone (MZ) and MZ precursor B cells, but not on the bulk of newly formed B cells, follicular B cells, germinal center B cells, and plasma cells. In the peritoneal cavity, FcRH3 was found on B1 cells, and not on the majority of B2 cells. Consistent with its possession of an ITIM and ITAM-like sequence, FcRH3 was tyrosine phosphorylated following pervanadate treatment, and its coligation with the BCR inhibited calcium mobilization. These results suggest FcRH3 is a novel immunoregulatory marker of MZ and B1 B lineage cells.

Recent studies have implicated a role for Notch in the generation of marginal zone (MZ) B cells. To further investigate the role of Notch in the B cell lineage, we have analyzed the effects of reduced Notch2 signaling in mice expressing one functional allele of Notch2 (Notch2(+/-)). Notch2(+/-) mice have reduced B1 B cells of the peritoneal cavity and show a severe reduction in MZ B cells of the spleen. The reduction in MZ B cells was not due to the disruption of splenic architecture, disregulated terminal differentiation, nor to increased apoptosis within the MZ B cell compartment. Rather, our data suggest that Notch2 haploinsufficiency leads to impaired development of MZ B cells, possibly by impacting the formation of immediate MZ B precursors. These results provide evidence that Notch2 plays a determining role in the development and/or the maintenance of B1 B and MZ B cells.

Marginal zone (MZ), follicular (FO), and B1 B cells form the long-lived naive B cell compartment. To identify surface markers that define MZ B cells in mice, we generated a panel of mAbs reactive with MZ but not FO B cells. One of these mAbs, MZ3, was found to recognize the tetraspanin CD9. CD9 expression not only distinguishes MZ B cells from FO B cells but also divided peritoneal cavity B1 cells into smaller subsets. After short-term in vitro stimulation with various mitogens, FO B cells failed to induce CD9 protein, while MZ B cells up-regulated the level of CD9 protein. However, after prolonged culture of FO B cells with LPS, surface CD9 was induced, together with syndecan 1, indicative of plasma cell differentiation. Following immunization with a T-independent-2 Ag, R36A, or a T-dependent Ag, SRBC, we found that CD9 is not expressed by germinal center B cells but is eventually expressed on plasma cells in response to both T-independent-2 and T-dependent Ags. Collectively, these results suggest that MZ B cells and B1 cell subsets are the immediate precursors of plasma cells in the primary response and that CD9 is acquired by T-dependent plasma cells.

The generation of VH81X heavy chain lambda-light chain-expressing B cells (VH81X-lambda+ B cells) was studied in VH81X heavy chain transgenic mice as well as in VH81X JH (-/-) and VH81X JH (-/-) Ck (-/-) mice, in which competition resulting from expression of heavy and light chains from the endogenous heavy and kappa light chain loci was prevented. We show that although lambda light chain gene rearrangements occur normally and give rise to light chains that associate with the transgenic heavy chain to form surface and soluble IgM molecules, further B cell development is almost totally blocked. The few VH81X-lambda+ B cells that are generated progress into a mature compartment (expressing surface CD21, CD22, CD23, and low CD24 and having a relatively long life span) but they also have reduced levels of surface Ig receptor and express higher amounts of Fas Ag than VH81X-kappa+ B cells. These VH81X-lambda+ B cells reach the peripheral lymphoid organs and accumulate in the periarteriolar lymphoid sheath but are unable to generate primary B cell follicles. In other heavy chain transgenic mice (MD2, M167, and M54), lambda+ B cells are generated. However, they seem to be preferentially selected in the peripheral repertoire of some transgenic heavy chain mice (M54) but not in others (MD2, M167). These studies show that a crucial selection step is necessary for B cell survival and maintenance in which B cells, similar to T cells, receive signals depending on their clonal receptors.

The development and establishment of the B Cell Repertoire is the net result of both genetic and environmental forces. The primary event at the genetic level is Ig gene rearrangement resulting in numerous possible combination of genes which can be further modified by somatic events such as N segment addition and somatic mutation. Environmental forces in the form of self and exogenous Ags also shape the repertoire by positively or negatively selecting B cells according to the specificity of their Ig receptors. These are dynamic processes beginning with the earliest expression of immunoglobulins in fetal life and continuing throughout life. In this review we discuss the genetic and selective mechanisms responsible for differences in the early immune system compared to that of the adult.