Control of B Cells Expressing Naturally Occurring Autoantibodies

ABSTRACT Sera from normal adult humans may contain high levels of antibody reactive with Candida albicans mannan. This study examined selected biological activities of such antibodies, focusing on sera that were collected from 34 donors and analyzed individually. The results showed that antimannan titers were normally distributed. Reactivity as determined by enzyme-linked immunosorbent assay with serotype A mannan generally paralleled reactivity with serotype B. Analysis of the kinetics for activation of the complement system and deposition of complement component 3 (C3) onto serotype A and serotype B cells showed a decrease in the lag time that occurred before the onset of rapid accumulation of C3 that correlated with increasing antimannan titers. In contrast, there was a decrease in the overall rate of accumulation of C3 on serotype A cells that was strongly correlated with increasing antibody titers; serotype B cells showed no such decrease. An evaluation of the contribution of mannan antibody to opsonophagocytic killing showed that mannan antibody in individual sera and antimannan immunoglobulin G (IgG) affinity purified from human plasma contributed to killing by neutrophils in a dose-dependent fashion in the absence of a functional complement system. However, affinity-purified antibody in very high concentrations was inhibitory to both complement-dependent and complement-independent opsonophagocytosis, and this finding suggests a prozone-like effect. In contrast, if the complement system was functional, antimannan IgG was not needed for opsonophagocytic killing. These results suggest that naturally occurring mannan antibodies and the complement system are functionally redundant for opsonophagocytic killing by neutrophils.

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Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-β

European Journal of Immunology ◽

10.1002/eji.200838193 ◽

2008 ◽

Vol 38 (11) ◽

pp. 3101-3113 ◽

Cited By ~ 72

Author(s):

Judith S. Satoguina ◽

Tomabu Adjobimey ◽

Kathrin Arndts ◽

Jochen Hoch ◽

Johannes Oldenburg ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Naturally Occurring

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Naturally Occurring Regulatory T Cells Modulate Immune Responses Against Exogenous Factor VIII in Hemophilic Balb/c Mice but Not in C57BL/6J Mice.

Blood ◽

10.1182/blood.v110.11.1160.1160 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1160-1160

Author(s):

Christina Hausl ◽

Josenato Ilas ◽

Christian Lubich ◽

Rafi U. Ahmad ◽

Eva M. Muchitsch ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Factor Viii ◽

Matched Control ◽

Antibody Responses ◽

Protein Antigens ◽

Naturally Occurring

Abstract Antibody responses against factor VIII (FVIII) are the major complication that arises when patients with hemophilia A are treated with factor VIII products. Therefore, understanding regulation of anti-FVIII immune responses is of outmost importance. Antibody responses are well established to result from differentiation of B cells into antibody-secreting plasma cells. B cells need help from activated CD4+ T cells to develop high-affinity antibody responses against protein antigens such as FVIII. Recently, naturally occurring CD4+CD25+ regulatory T cells have been shown to modulate antibody responses by either suppressing the function of CD4+ T helper cells or by directly acting on B cells. However, the potential importance of CD4+CD25+ T cells in regulating antibody responses to foreign protein antigens is controversial. Furthermore, the extent to which naturally occurring CD4+CD25+ T cells regulate antibody responses against exogenous proteins such as FVIII when these proteins are given to previously untreated patients is unclear. To obtain information on how important naturally occurring CD4+CD25+ T cells are under such conditions, we asked whether these cells regulate anti-FVIII antibody responses in murine hemophilia A. We studied E17 hemophilic mice with two different genetic backgrounds (C57BL/6J and Balb/c) and treated them with four intravenous doses of human FVIII given at weekly intervals. Before the first dose of FVIII, CD4+CD25+ T cells were depleted in vivo using an anti-CD25 antibody that has been shown to deplete naturally occurring CD4+CD25+ T cells in mice. In vivo depletion of regulatory T cells using the same antibody has been successfully applied in a variety of mouse studies to evaluate the significance of naturally occurring CD4+CD25+ T cells in different immunological systems. An isotype-matched control antibody was used as a negative control. A week after the second and the fourth dose of FVIII, plasma samples were taken and tested for anti-FVIII antibodies. We found differences in titers of anti-FVIII antibodies between mice treated with anti-CD25 antibodies and control mice in Balb/c mice but not in C57BL/6J mice. Hemophilic Balb/c mice that had been pre-treated with anti-CD25 antibodies developed higher titers of anti-FVIII antibodies than mice that had been pre-treated with an isotype-matched control antibody. Differences were seen as a statistical trend (p=0.091) after two doses of FVIII and reached statistical significance (p=0.024) after four doses of FVIII. No differences in antibody titers were observed in hemophilic C57BL/6J mice. Our results strongly indicate that the ability of naturally occurring regulatory T cells to modulate anti-FVIII antibody responses in hemophilic mice depends on the genetic background of these mice. Immunoregulatory factors such as cytokines or chemokines as well as differences in the number and functional activity of naturally occurring regulatory T cells that are found in secondary lymphoid organs are likely to determine the regulatory capacity of these cells. Based on our results we conclude that differences in number and functional activity of naturally occurring regulatory T cells should be considered in the search for risk factors associated with the development of FVIII inhibitors in patients.

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Naturally occurring human phosphorylcholine antibodies are predominantly products of affinity-matured b cells in the adult

Atherosclerosis ◽

10.1016/j.atherosclerosis.2014.05.423 ◽

2014 ◽

Vol 235 (2) ◽

pp. e149

Author(s):

R. Fiskesund ◽

J. Steen ◽

K. Amara ◽

F. Murray ◽

A. Szwajda ◽

...

Keyword(s):

B Cells ◽

Naturally Occurring

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B-cell anergy: from transgenic models to naturally occurring anergic B cells?

Nature Reviews Immunology ◽

10.1038/nri2133 ◽

2007 ◽

Vol 7 (8) ◽

pp. 633-643 ◽

Cited By ~ 228

Author(s):

John C. Cambier ◽

Stephen B. Gauld ◽

Kevin T. Merrell ◽

Barbara J. Vilen

Keyword(s):

B Cells ◽

B Cell ◽

Transgenic Models ◽

Naturally Occurring ◽

Cell Anergy ◽

B Cell Anergy

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Unexpectedly Weak Anti-B in 2 Group O Pediatric Patients on Parenteral Nutrition and Disease Specific Supplemental Enteral Feeds

Laboratory Medicine ◽

10.1093/labmed/lmz057 ◽

2019 ◽

Vol 51 (3) ◽

pp. 296-300

Author(s):

Alesia Kaplan ◽

Kimberly A Gabert ◽

Mark H Yazer

Keyword(s):

B Cells ◽

Parenteral Nutrition ◽

Pediatric Patients ◽

Intestinal Bacteria ◽

Healthy Person ◽

Blood Type ◽

Bone Marrow Transplants ◽

Naturally Occurring ◽

Clinical Scenarios ◽

Disease Specific

Abstract Anti-A and anti-B antibodies are naturally occurring and develop from exposure to intestinal bacteria after age 4 to 6 months. In the laboratory, strong agglutination with A1 and B cells, or B cells only and A1 cells only, on reverse typing in a healthy person with immunocompetence is expected for patients with ABO types O, A, and B, respectively. However, absent or weak anti-A and anti-B antibodies can be observed in some clinical scenarios, such as patients with immunodeficiencies, newborns, elderly patients, and patients who have recently received bone marrow transplants. In this article, we report the cases of 2 pediatric patients with group O blood type who were receiving total parenteral nutrition (TPN) and disease-specific enteral feeds and who have strong anti-A and absent/weak anti-B.

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B cell–deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis

Journal of Experimental Medicine ◽

10.1084/jem.20051438 ◽

2006 ◽

Vol 203 (2) ◽

pp. 349-358 ◽

Cited By ~ 61

Author(s):

Shiguang Yu ◽

Prasanta K. Maiti ◽

Melissa Dyson ◽

Renu Jain ◽

Helen Braley-Mullen

Keyword(s):

B Cells ◽

B Cell ◽

Autoimmune Thyroiditis ◽

T Regulatory Cells ◽

Effector T Cells ◽

Regulatory Cells ◽

Wild Type ◽

Naturally Occurring ◽

Deficient Mice

Wild-type (WT) NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) when given 0.05% NaI in their drinking water, whereas B cell–deficient NOD.H-2h4 mice are SAT resistant. To test the hypothesis that resistance of B cell–deficient mice to SAT was due to the activity of regulatory CD4+CD25+ T (T reg) cells activated if autoantigen was initially presented on non–B cells, CD25+ T reg cells were transiently depleted in vivo using anti-CD25. B cell–deficient NOD.H-2h4 mice given three weekly injections of anti-CD25 developed SAT 8 wk after NaI water. Thyroid lesions were similar to those in WT mice except there were no B cells in thyroid infiltrates. WT and B cell–deficient mice had similar numbers of CD4+CD25+Foxp3+ cells. Mice with transgenic nitrophenyl-specific B cells unable to secrete immunoglobulin were also resistant to SAT, and transient depletion of T reg cells resulted in severe SAT with both T and B cells in thyroid infiltrates. T reg cells that inhibit SAT were eliminated by day 3 thymectomy, indicating they belong to the subset of naturally occurring T reg cells. However, T reg cell depletion did not increase SAT severity in WT mice, suggesting that T reg cells may be nonfunctional when effector T cells are activated; i.e., by autoantigen-presenting B cells.

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