Defects In B-cell Function Research Articles

B-cell abnormalities in HIV-1 infection: roles for IgG3 and T-bet.

Numerous B-cell abnormalities in HIV-1 infection have been described over the past three decades yet have remained poorly defined mechanistically. We review recent studies that describe mechanisms of B-cell dysregulation in chronic HIV-1 infection associated with IgG3 and T-bet. HIV-1 infection causes hypergammaglobulinemia and dysregulation of B-cell populations, including the expansion during chronic viremia of functionally impaired tissue-like memory (TLM) B cells. TLM B cells and B cells in other conditions of chronic activation and inflammation with similar phenotypes are characterized by increased expression of the transcription factor T-bet and preferential immunoglobulin class-switching to IgG3. However, defects in B-cell function during chronic HIV-1 viremia are also associated with the binding of soluble IgG3 to IgM-expressing B cells, with the highest intensities observed on TLM B cells. The consequence of IgG3 binding to TLM B cells is increased clustering of the IgM B-cell receptor and decreased response to stimulation. The identification of T-bet and IgG3 as the regulators of B-cell function in chronic HIV-1 viremia could provide new targets for therapeutic intervention aimed at reversing the damaging effects of HIV-1-associated chronic immune activation.

Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage

During our life, we are surrounded by continuous threats from a diverse range of invading pathogens. Our immune system has evolved multiple mechanisms to efficiently deal with these threats so as to prevent them from causing disease. Terminal differentiation of mature B cells into plasma cells (PC) – the antibody (Ab) secreting cells of the immune system – is critical for the generation of protective and long-lived humoral immune responses. Indeed, efficient production of antigen (Ag)-specific Ab by activated B cells underlies the success of most currently available vaccines. The mature B-cell pool is composed of several subsets, distinguished from one according to size, surface marker expression, location, and Ag exposure, and they all have the capacity to differentiate into PCs. For a B-cell to acquire the capacity to produce Abs, it must undergo an extensive differentiation process driven by changes in gene expression. Two broad categories of Ags exist that cause B-cell activation and differentiation: T cell dependent (TD) or T cell independent (TI). In addition to the B-cell subset and nature of the Ag, it is important to consider the cytokine environment that can also influence how B-cell differentiation is achieved. Thus, while many cytokines can induce Ab-secretion by B cells after activation with mimics of TD and TI stimuli in vitro, they can have different efficacies and specificities, and can often preferentially induce production of one particular Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role of different cytokines in inducing the differentiation of distinct B-cell subsets to the PC lineage. We will place particular emphasis on IL-21, which has emerged as the most potent inducer of terminal B-cell differentiation in humans. We will also focus on the role of IL-21 and defects in B-cell function and how these contribute to human immunopathologies such as primary immunodeficiencies and B-cell mediated autoimmune conditions.

Asymptomatic choroidal granulomas in common variable immunodeficiency

Common variable immunodeficiency disease represents the most common cause of significant antibody deficiency in adults. It is a heterogeneous group of disorders that can be sporadic or familial with various modes of inheritance with defects in B-cell function, regulatory T-cells and macrophage function all being reported. Herein a case of asymptomatic bilateral choroidal granulomatous disease in a 27-year-old man with common variable immunodeficiency disease is described.

Role of zeta PKC in B-cell signaling and function.

The atypical protein kinase C isoform, zeta PKC, has been implicated in the control of extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-kappa B pathways. Recent evidence from zeta PKC knock-out mice demonstrates that this kinase is important for NF-kappa B transcriptional activity but not for ERK activation in embryonic fibroblasts. The lack of zeta PKC produces in mice a number of alterations in the development of secondary lymphoid tissues that could be accounted for, at least in part, by defects in B-cell function. Here, we present evidence that the loss of zeta PKC selectively impairs signaling through the B-cell receptor, resulting in inhibition of cell proliferation and survival, as well as defects in the activation of ERK and the transcription of NF-kappa B-dependent genes. Furthermore, zeta PKC-/- mice are unable to mount an optimal T-cell-dependent immune response. Collectively, these results genetically establish a critical role for zeta PKC in B-cell function in vitro and in vivo.

Defects in B-cell function and metabolism in uremia: Role of parathyroid hormone

Patients with chronic renal failure have impaired humoral immunity, inadequate B-cell proliferation and antibody production, and elevated basal levels of cytosolic calcium ([Ca2+]i) in their B cells. Multiple mechanisms can be involved in generation of these derangements. This article reviews data suggesting that high levels of parathyroid hormone (PTH) of uremia affect the metabolism and function of B cells. We also review studies on the role of normalization of [Ca2+]i in these abnormalities. Small but well-documented studies suggest that treatment of dialysis patients with calcium channels blockers can reverse the elevation of [Ca2+]i in B cells, which was followed by improvement of B-cell function. Thus, therapy with calcium channel blockers has the potential to decrease the infectious complication of uremia.

Defects in B-cell function and metabolism in uremia: Role of parathyroid hormone

Defects in B-cell function and metabolism in uremia: Role of parathyroid hormone

Influence of continuous, very low-dose gamma-irradiation on the mouse immune system

Purpose : To investigate whether continuous, very low-dose γ-irradiation (10 cGy/year) modifies immune parameters in mice. Material and methods : C57BL/6 female mice, 4 weeks old, were irradiated for 24 months and compared with control mice living in the same room. B- and T-cell subsets were evaluated by flow cytometry before and after stimulation with lectins; subclasses of immunoglobulins were determined by ELISA 2, 4, 6, 8, 12, 18 and 24 months after the beginning of the irradiation. Results : No difference was found in the percentage of CD4 + and CD8 + cells in the thymus and the spleen, or in the reactivity of T-cells to lectins. While the number of B-cells in the spleen remained unchanged, a significant decrease of IgG1, IgG2b and IgG2a was observed after respectively 12, 18 and 24 months of irradiation. Conclusion : The parameters of cellular immunity studied were not affected by this chronic low-dose of irradiation, but this dose rate is probably too low to induce the hormetic effect previously described. Further investigations are necessary to assess whether the decline of immunoglobulin secretion is indicative of a lower rate of infectious diseases or a defect in B-cell function.

Modulation of B-cell abnormalities in lupus-prone (NZB x NZW) F1 mice by normal bone marrow-derived B-lineage cells

(NZB x NZW)F1(NZB/WF1) mice spontaneously develop an autoimmune disease characterized by abnormality of haemopoietic stem cells. The present study examined a possible regulatory cell interaction between NZB/WF1 and normal bone marrow cells using radiation-induced chimeras. We demonstrated that the ability of NZB/WF1 bone marrow cells to transfer the typical disease with hypergammaglobulinemia including autoantibodies into lethally irradiated normal recipients was prevented by cotransfer of bone marrow from normal CBA/J mice but not from xid CBA/N mice carrying a selective defect in B-cell function. Flow cytometric analysis revealed that the generation of NZB/WF1 cells was reduced in the mixed chimeras given CBA/J but not CBA/N bone marrow cells. Interestingly, radiation chimeras reconstituted with a mixture of NZB/WF1 bone marrow and CBA/J splenic B cells did not show elevation of serum immunoglobulin levels, although most of the spleen cells were dominated by NZB/WF1 cells. On the other hand, NZB/WF1 B cells maturated in vivo in the presence of CBA/J bone marrow or splenic B cells lost the hyper-responsiveness to lipopolysaccharide (LPS) in the autoantibody production in vitro. These results suggest that radiosensitive normal B-lineage cells have the regulatory activity to ameliorate the hypergammaglobulinemia of NZB/WF1 mice by reducing the generation of NZB/WF1 B cells and/or by correcting their hyper-responsiveness, and that NZB/WF1 mice may have a defect(s) in the regulatory cell function. In addition, CBA/J splenic B cells were shown to modulate the B-cell abnormality even when injected into non-irradiated NZB/WF1 mice manifesting autoimmunity.

Bacterial pneumonia in adult patients with HIV infection.

Patients with HIV infection are at increased risk for community-acquired bacterial pneumonias, due in part to their defects in B-cell function. Streptococcus pneumoniae is the commonest cause of community-acquired pneumonia, with the second most common bacterial agent being Haemophilus influenzae. These two organisms account for about two-thirds of community-acquired bacterial pneumonias. Frequently bacterial pneumonias appear difficult to distinguish from Pneumocystis carinii pneumonia or other opportunistic lung infections, because of their atypical clinical and radiologic presentations. Community-acquired pneumonias may be recurrent but have low fatality rates. In comparison, nosocomial pneumonias occur primarily in patients with AIDS and are usually due to Staphylococcus aureus, Pseudomonas aeruginosa and other aerobic gram-negative bacilli. Nosocomial pneumonias have high fatality rates. S.aureus is an important cause of morbidity and mortality in patients with AIDS and has emerged as a secondary opportunist in lungs of patients with opportunistic diseases. While appropriate laboratory study is being done, empiric antibiotic therapy should be directed against the microorganisms above described.

X-linked agammaglobulinemia: new approaches to old questions based on the identification of the defective gene.

The identification of a cytoplasmic tyrosine kinase, Btk, as the defective protein in human XLA and xid in the mouse, supports the hypothesis that both disorders are due to defects in B-cell activation or differentiation. Phenotypic analysis of B-lineage cells and studies on X-chromosome inactivation patterns in both mice and human patients suggest that mutations in Bth do not affect entry of stem cells into the B-lineage pathway but they do inhibit progression at multiple steps along that pathway. Although the exact function of Btk in signal transduction is not yet known, it is probable that studies which correlate specific mutations in different patients with alterations in Btk function will provide clues about critical sites in the molecule. Diagnosis and genetic counseling for families at risk of carrying the gene for XLA will be improved almost immediately by the identification of the responsible gene. Improvements in therapy may come more slowly. The possibility of curative gene therapy is attractive; however, there are several features of Btk that suggest that this will be a challenging undertaking. Overexpression or expression in inappropriate cell lineages may carry unacceptable risks. Mutant proteins may interfere with the function of wild-type proteins provided by gene therapy. However, it is likely that a better understanding of Btk function and regulation will benefit not only patients with XLA but also other patients with defects in B-cell function.

Infections in AIDS Patients

In the absence of a specific diagnostic test for AIDS, a case can be recognized only when complications of the immune deficiency such as opportunistic infections or Kaposi's sarcoma occur. Defective T-cell function is the principal immunological defect; however, there are defects in B-cell function which may have some clinical significance. It has not been possible to reverse the immunological deficiency in AIDS patients. These patients remain susceptible to a succession of infections to which they ultimately succumb. Effective treatment is available for many of the infectious complications of AIDS.

Long-term function of duct-ligated and free-duct whole pancreas transplants

This report compares endocrine and exocrine responses of “free-duct” and “duct-ligated” whole pancreas isografts in Lewis diabetic rats during a 1-year period of observation. Fasting blood sugar, serum amylase, serum insulin, pancreozymin-secretin test, and l-arginine tolerance test assays were performed prior to and at periodic intervals after transplantation. Histological examinations of transplanted and native pancreas were performed monthly on animals in each group. Whole pancreas transplantations led to immediate and sustained normalization of FBS and insulin levels. In the “duct-ligated” group there was a gradual but insignificant decrease of serum insulin levels after 9 months. Depressed serum amylase levels in diabetic rats were reversed in both groups. Isolated islet iso- and allografts also reversed depressed amylase levels. The results of pancreozymin-secretin tests in islet isografted animals supported the postulated trophic effect of endocrine pancreas on exocrine pancreas. Although both whole-pancreas transplant groups showed a normal response to GTT for 12 months after transplantation, the “duct-ligated” group showed a significantly lower response to l-arginine tolerance test than the “free duct” model as early as 4 months after transplantation, suggesting a defect in B-cell function in long-term “duct-ligated” graft. Serial histological examinations of transplanted pancreases revealed more rapid atrophy and more intense fibrosis of acinar tissue in the “duct-ligated” group than in the “free duct” group. These results suggest that a “free duct” pancreatic isograft maintains a more stable endocrine function in a long-term study than does the “duct-ligated” pancreas, and that exocrine dysfunction in diabetic rats may be related to the endocrine disorder which can be reversed by both islet cell and whole-organ pancreatic transplantation.

Community-acquired bacterial pneumonias in homosexual men: presumptive evidence for a defect in host resistance.

Over a three year period, we encountered seven homosexual men who developed pneumonias due to S. pneumoniae or H. influenzae in the absence of apparent risk factors. When compared to heterosexual controls, the homosexual group had a much higher frequency of bacteremia, complicated primary infections, multilobar involvement, required longer antibiotic therapy, and took longer to defervesce. Three of our seven homosexual patients fulfilled criteria for the acquired immunodeficiency syndrome (AIDS); two of the others had generalized lymphadenopathy and the other two likely AIDS-related abnormalities. Overall they presented with a spectrum of clinical findings. Two of the patients developed other opportunistic infections associated with AIDS. Since recovery from these pyogenic pneumonias requires an appropriate antibody response, our patients may have had a defect in B-cell function. Moreover, these observations suggest that functional B-cell abnormalities may occur in AIDS and syndromes premonitory of AIDS.

Selective immunoglobulin M deficiency in an adult: Assessment of immunoglobulin production by peripheral blood lymphocytes in vitro

A patient with a selective IgM deficiency had normal numbers of circulating lymphocytes, sheep red blood cell rosetting T cells, and B cells bearing surface IgG and IgA; IgM staining B cells were absent. Upon in vitro stimulation, the patient's peripheral blood lymphocytes produced normal amounts of IgG and IgA but the IgM response was in the low range of normal. In the patient's blood, no evidence was found for the presence of a circulating IgG inhibitor of IgM synthesis by either autologous or allogeneic lymphocytes. The results of mixtures of patient and control lymphocytes provided no evidence for the presence of either a lymphocyte suppressor of immunoglobulin synthesis or a lack of helper cell function. The failure to demonstrate absolute defects in B-cell function or T-cell-modulating function would suggest alternative explanations for this and other forms of dysgammaglobulinemia.

902 MONOCYTE SUPPRESSION OF IMMUNOGLOBULIN SECRETION IN A 9-YEAR-OLD BOY WITH SCID

We report the evaluation of in vitro immunoregulation in a 9-year-old untreated boy with SCID. Ficoll-Hypaque-isolated peripheral blood mononuclear cells (MNL) from the patient failed to respond to pokeweed mitogen (PWM) with the normal increment in immunoglobulin-secreting cells (Ig-SC), as measured by a reverse hemolytic plaque assay. Removal of phagocytic cells or the addition of unrelated irradiated helper cells resulted in enhanced, but still suboptimal response to PWM, suggesting some intrinsic defect in B-cell function. Co-culture of patient with normal MNL resulted in marked (88%) suppression of PWM-induced Ig-SC. Suppressor activity was unaffected by prior irradiation of patient MNL, but was substantially reversed (32% net enhancement) by removal of his phagocytic cells; whereas the combination of the two procedures further reversed suppression (52% net enhancement). Because the patient was lymphopenic, his MNL were relatively enriched for monocytes (range=40-80%). To determine whether the suppressor cell activity was due to functional or numerical excess of patient monocytes, co-cultures were performed using varying ratios of patient to normal MNL. Suppression was most marked in cultures containing >40% monocytes, suggesting that a numerical excess of patient monocytes could account for the observed suppression. These data suggest both an intrinsic defect in B-cell function, and a relative numerical excess of monocytes which could further inhibit Ig-secretion by B-cells.