Effects of Cancer Therapies on Immunoglobulin Synthesis: A Review of Mechanisms, Clinical Implications, and Mitigation Strategies.

Management of secondary immune deficiencies

Immunology

N-3 polyunsaturated fatty acids modulate B cell activity in pre-clinical models: Implications for the immune response to infections

Natural antibodies are present in the serum of individuals in the absence of known antigenic stimulation. These antibodies are primarily IgM, polyreactive, and encoded by immunoglobulin V genes in germline configuration. Natural antibodies are produced by B-1 lymphocytes, cells that form the primary cell of the fetal and newborn B cell repertoire and may represent the basic foundation upon which the adult repertoire of B cell antibodies is based. Natural antibodies react with a variety of endogenous and exogenous antigens, including xenoantigens expressed by tissues between unrelated species. These antibodies are capable of causing the immediate rejection of grafts exchanged across species barriers. One of the central issues related to our understanding of the immunopathologic mechanisms responsible for rejection of xenografts is whether pre-formed natural antibodies and new antibodies induced following xenotransplantation are produced by the same pathways of B cell antibody production. We have established in studies conducted in rodents and humans that the initial phases of antibody production xenogeneic tissues involves the use of a restricted population of Ig germline genes to encode xenoantibody binding. As the humoral xenoantibody response matures, the same closely-related groups of Ig V genes are used to encode antibody binding and there is evidence for an isotype switch to IgG antibody production and the appearance of somatic mutations consistent with antigen-driven affinity maturation. Our findings in both rodent and human studies form the basis for our proposal that the xenograft response reflects the use of B cell natural antibody repertoires originally intended to provide protection against infection. The host humoral response is inadvertently recruited to mount antibody responses against foreign grafts because they display carbohydrate antigens that are shared by common environmental microbes. This model of xenoantibody responses is being tested in our laboratory through the analysis of the binding of xenoantibodies in their original non-mutated configuration, and the examination of the effect of specific point mutations and gene shuffling have on xenoantibody binding activity. Establishment of the relationships between Ig structural changes and subsequent changes in binding affinity should provide important insights into the role that, natural antibodies and the cells that produce them play in the evolution of the host's humoral responses to xenografts.

BackgroundDifferences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiota on humoral immune activation.MethodsMale and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed, and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotype. The functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, was evaluated ex vivo using mitogen stimulation of B cells. Additional influences of the gut microbiome on sex chromosome-dependent B cell activation was also evaluated by antibiotically depleting gut microbiota prior to HKSP immunization. Reconstitution of the depleted microbiome with short-chain fatty acid (SCFA)-producing bacteria tested the impact of SCFAs on XX-dependent immune activation.ResultsXX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria enhanced fecal SCFA concentrations and increased humoral responses in XX, but not XY, FCG mice. However, exposure to the SCFA propionate alone did not enhance mitogenic B cell stimulation in ex vivo studies.ConclusionsFCG mice have been used to assess sex hormone and sex chromosome complement influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphism.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13293-024-00597-0.

CD59a deficient mice display reduced B cell activity and antibody production in response to T-dependent antigens

Relationship between hybridoma growth and monoclonal antibody production

Our current understanding of humoral immunity of poultry

X-linked lymphoproliferative disease is caused by mutations affecting SH2D1A/SAP, an adaptor that recruits Fyn to signal lymphocyte activation molecule (SLAM)-related receptors. After infection, SLAM-associated protein (SAP)−/− mice show increased T cell activation and impaired humoral responses. Although SAP−/− mice can respond to T-independent immunization, we find impaired primary and secondary T-dependent responses, with defective B cell proliferation, germinal center formation, and antibody production. Nonetheless, transfer of wild-type but not SAP-deficient CD4 cells rescued humoral responses in reconstituted recombination activating gene 2−/− and SAP−/− mice. To investigate these T cell defects, we examined CD4 cell function in vitro and in vivo. Although SAP-deficient CD4 cells have impaired T cell receptor–mediated T helper (Th)2 cytokine production in vitro, we demonstrate that the humoral defects can be uncoupled from cytokine expression defects in vivo. Instead, SAP-deficient T cells exhibit decreased and delayed inducible costimulator (ICOS) induction and heightened CD40L expression. Notably, in contrast to Th2 cytokine defects, humoral responses, ICOS expression, and CD40L down-regulation were rescued by retroviral reconstitution with SAP-R78A, a SAP mutant that impairs Fyn binding. We further demonstrate a role for SLAM/SAP signaling in the regulation of early surface CD40L expression. Thus, SAP affects expression of key molecules required for T–B cell collaboration by mechanisms that are distinct from its role in cytokine regulation.

Applications of low-intensity pulsed ultrasound to increase monoclonal antibody production in CHO cells using shake flasks or wavebags

Regulatory T Cells: Key Controllers of Immunologic Self-Tolerance

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Knowledge of the molecular events regulating the innate response to Mycobacterium tuberculosis (Mtb) is critical for understanding immunological pathogenesis and protection from tuberculosis. To this aim, the regulation and the expression of regulatory and proinflammatory cytokines were investigated in human primary monocytes upon Mtb infection. We found that Mtb-infected monocytes preferentially express a proinflammatory cytokine profile, including IL-6, TNF-α, and IL-1β. Conversely, among the regulatory cytokines, Mtb elicited IL-10 and IL-23 release while no expression of IL-12p70, IL-27, and IFN-β was observed. The analysis of the signalling pathways leading to this selective cytokine expression showed that in monocytes Mtb activates MAPK and NF-κB but is unable to stimulate IRF-3 phosphorylation, a transcription factor required for IL-12p35 and IFN-β gene expression. Thus, by inducing a specific cytokine profile, Mtb can influence the immunoregulatory properties of monocytes, which represent important target of novel vaccinal strategies against Mtb infection.

Dissecting the components of the humoral immune response elicited by DNA vaccines

Thymosin effects on immunoglobulin synthesis and suppressor T cell activity in normal subjects and patients with primary biliary cirrhosis