B-lymphocytes, innate immunity, and autoimmunity

Viau, Muriel; Zouali, Moncef

doi:10.1016/j.clim.2004.08.019

Cited by 153 publications

(120 citation statements)

References 110 publications

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“…The decreased apoptosis has been linked to autoimmunity (30). Mutations in genes that regulate apoptosis, such as Fas, FasL, caspase 10, and caspase 8, result in higher susceptibility to autoimmune diseases (20,21,31,33,34).…”

Section: Discussionmentioning

confidence: 99%

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Iskander

Han

et al. 2006

Journal of Biological Chemistry

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NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) are cytosolic enzymes that catalyze metabolic reduction of quinones and derivatives. NQO1-null and NQO2-null mice were generated that showed decreased lymphocytes in peripheral blood, myeloid hyperplasia, and increased sensitivity to skin carcinogenesis. In this report, we investigated the in vivo role of NQO1 and NQO2 in immune response and autoimmunity. Both NQO1-null and NQO2-null mice showed decreased B-cells in blood, lower germinal center response, altered B cell homing, and impaired primary and secondary immune responses. NQO1-null and NQO2-null mice also showed susceptibility to autoimmune disease as revealed by decreased apoptosis in thymocytes and predisposition to collagen-induced arthritis. Further experiments showed accumulation of NADH and NRH, cofactors for NQO1 and NQO2, indicating altered intracellular redox status. The studies also demonstrated decreased expression and lack of activation of immune-related factor NF-B. Microarray analysis showed altered chemokines and chemokine receptors. These results suggest that the loss of NQO1 and NQO2 leads to altered intracellular redox status, decreased expression and activation of NF-B, and altered chemokines. The results led to the conclusion that NQO1 and NQO2 are endogenous factors in the regulation of immune response and autoimmunity.Quinone oxidoreductases (NQO1 and NQO2) 2 are cytosolic flavoproteins that catalyze two-electron metabolic reduction and detoxification of quinones and derivatives (1, 2). This leads to protection of cells against oxidative stress and neoplasia. However, in some cases, especially in the absence of conjugating reactions, the hydroquinones undergo oxidation to generate reactive oxygen species causing damage to cells (1, 2). NQO1-null and NQO2-null mice lacking respective gene expression showed alterations in intracellular redox status, myeloid hyperplasia, and higher susceptibility to skin carcinogenesis (3-7). Both NQO1-null and NQO2-null mice demonstrated lower expression and induction of tumor suppressor p53 (7,8). NQO1 protects p53 from ubiquitin-independent 20 S proteasomal degradation (9).A cytosine to thymidine (C 3 T) polymorphism in exon 6 of human NQO1 gene produces a proline to serine (P187S) substitution that destabilizes the protein (10, 11). Individuals carrying both mutated genomic alleles are completely lacking in NQO1 activity, whereas heterozygous individuals with one mutated allele have low-to-intermediate NQO1 activity as compared with wild-type individuals (12). Approximately 2-4% human individuals are homozygous and 20 -25% are heterozygous for this mutation (13-16).The roles of genetic factors in immune deficiency and autoimmune diseases have been recognized for decades (17). B cells play a key role in regulation of immune system. B cells produce antibodies, provide support to other mononuclear cells, and contribute directly to inflammatory pathways (18). Impaired B cell production, maturation, homing, and activation are...

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Section: Discussionmentioning

confidence: 99%

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Iskander

Han

et al. 2006

Journal of Biological Chemistry

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“…Autoantibody mediated tissue destruction is among the main features of organ-specific autoimmunity (29). Since the original discovery of catalytic antibodies (30)(31)(32), ample data established their contribution to pathological effects in disease (33) as well as their possible biomedical applications (23,34).…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Пономаренко

Durova

Vorobiev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

174

236

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Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes ''an antibody enzyme'' (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP 85-101 peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibodymediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.

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“…In particular, significant expansion of MZ B cells is observed in New Zealand Black (NZB), (NZB 3 New Zealand White [NZW])F 1 , MRL-lpr, and B cell-activating factor belonging to the TNF family (BAFF; TNFSF13B) transgenic (BAFFTg) mouse strains (6)(7)(8). In these models, MZ B cells contribute to autoimmune pathology by harboring increased proportions of clones displaying self-reactive BCR specificities that produce significant quantities of autoantibodies and infiltrate target organs (9). B cells exhibiting a MZ phenotype also form a significant part of the target organ infiltrate in patients developing Sjögren's syndrome and Grave's disease (10,11).…”

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confidence: 99%

Intrinsic Molecular Factors Cause Aberrant Expansion of the Splenic Marginal Zone B Cell Population in Nonobese Diabetic Mice

Stolp

Mariño

Batten

et al. 2013

The Journal of Immunology

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Marginal zone (MZ) B cells are an innate-like population that oscillates between MZ and follicular areas of the splenic white pulp. Differentiation of B cells into the MZ subset is governed by BCR signal strength and specificity, NF-κB activation through the B cell–activating factor belonging to the TNF family (BAFF) receptor, Notch2 signaling, and migration signals mediated by chemokine, integrin, and sphingosine-1-phosphate receptors. An imbalance in splenic B cell development resulting in expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models. One example is the NOD inbred mouse strain, in which MZ B cell expansion has been linked to development of type 1 diabetes and Sjögren’s syndrome. However, the cause of MZ B cell expansion in this strain remains poorly understood. We have determined that increased MZ B cell development in NOD mice is independent of T cell autoimmunity, BCR specificity, BCR signal strength, and increased exposure to BAFF. Rather, mixed bone marrow chimeras showed that the factor(s) responsible for expansion of the NOD MZ subset is B cell intrinsic. Analysis of microarray expression data indicated that NOD MZ and precursor transitional 2-MZ subsets were particularly dysregulated for genes controlling cellular trafficking, including Apoe, Ccbp2, Cxcr7, Lgals1, Pla2g7, Rgs13, S1pr3, Spn, Bid, Cd55, Prf1, and Tlr3. Furthermore, these B cell subsets exhibited an increased steady state dwell time within splenic MZ areas. Our data therefore reveal that precursors of mature B cells in NOD mice exhibit an altered migration set point, allowing increased occupation of the MZ, a niche favoring MZ B cell differentiation.

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B-lymphocytes, innate immunity, and autoimmunity

Cited by 153 publications

References 110 publications

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen

Intrinsic Molecular Factors Cause Aberrant Expansion of the Splenic Marginal Zone B Cell Population in Nonobese Diabetic Mice

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