[show abstract][hide abstract] ABSTRACT: To determine whether Finegoldia magna protein L (PL) causes lung inflammation and, if so, whether the response is dependent on its immunoglobulin (Ig)-binding B-cell superantigenic property.
Pulmonary inflammatory reactions were analyzed at various time points after intratracheal administration of PL to various strains of mice.
PL caused peribronchial and perivascular inflammation that peaked at 18-24 h. Polymorphonuclear cells (PMNs) began to accumulate in bronchoalveolar lavage fluid (BALF) of PL-challenged mice by 4 h and accounted for >90% of leukocytes by 18-24 h. Inflammation was marked by the appearance of MIP-2, KC, TNF-α, and IL-6 in the BALF with peak levels attained 4 h after PL administration. PL-induced pulmonary inflammation was associated with increased airway hyper-reactivity following inhalation of methacholine. The inflammatory reaction was unabated in mice lacking B cells and immunoglobulins. In contrast, PL-induced inflammation was abrogated in MyD88-deficient mice. PL-induced responses required alveolar macrophages.
These results strongly suggest that PL-induced lung inflammation is dependent on an innate MyD88-dependent pathway rather than the Ig-binding properties of this microbial B cell superantigen. We propose that this pulmonary inflammatory reaction is caused by the interaction of PL with a Toll-like receptor expressed on alveolar macrophages.
Agents and Actions 02/2012; 61(2):161-9. · 1.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Toll-like receptors contribute to the establishment of adaptive immune responses.
The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation.
Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR.
Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts.
Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.
The Journal of allergy and clinical immunology 12/2008; 123(1):224-230.e4. · 9.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is a large body of circumstantial evidence highlighting a primary role of the thymus in the pathogenesis of MG. Nevertheless,
the etiologic link remains to be forged. We are reexamining the hypothesis that AChR expressed in the thymus drives the pathogenic
autoimmune response. To this end, we have established a model of intrathymic inflammation that is localized to the thymic
medulla and demonstrated that this inflammatory process promotes the nonspecific entry of peripheral CD4+ T cells into the thymus. Using this model, we are in the process of determining whether (a) AChR-reactive CD4+ T cell homing to the thymus is augmented by a concurrent intrathymic inflammatory response to an unrelated antigen, and (b)
AChR-reactive T cell immigrants undergo activation following their engagement of autoantigen in this inflammatory milieu,
provide help for the production of anti-AChR antibodies by immigrant autoreactive B cells, and thereby promote the development
of a myasthenic syndrome.
[show abstract][hide abstract] ABSTRACT: The thymus is considered to play an important role in the pathogenesis of Myasthenia gravis, an autoimmune disease characterized by antibody-mediated skeletal muscle weakness. However, its role is yet to be defined. The studies described herein summarize our efforts to determine how intrathymic expression of the neuromuscular type of acetylcholine (ACh) receptors is involved in the immunopathogenesis of this autoimmune disease. We review the work characterizing the expression of neuromuscular ACh receptors in the thymus and advance a new hypothesis that examines the intrathymic expression of this autoantigen in disease pathogenesis.
Clinical and Developmental Immunology 01/2004; 11(3-4):215-20. · 3.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: The thymus is thought to play an important role in the pathogenesis of myasthenia gravis (MG), an autoimmune disease characterized by skeletal muscle weakness. However, its role remains a mystery. The studies described represent our efforts to determine how intrathymic expression of the neuromuscular type of acetylcholine receptors (nAChRs) is involved in the immunopathogenesis of MG. We review our work characterizing the expression of the alpha subunit of nAChR (nAChRalpha) in the thymus and advance a new hypothesis that examines the intrathymic expression of this autoantigen in disease pathogenesis.
Annals of the New York Academy of Sciences 10/2003; 998:257-65. · 4.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: The thymus has been considered to play an important role in the pathogenesis of myasthenia gravis (MG), an autoimmune disease characterized by skeletal muscle weakness. However, the pathogenic role of the thymus still remains a mystery. The neuromuscular type of acetylcholine receptor (AChR) was the first self-protein associated with a defined autoimmune disease that was found to be expressed by thymic stromal populations. The studies described herein represent our efforts to determine how this "promiscuous" autoantigen expression may be involved in the immunopathogenesis of MG. We review our work, characterizating the expression of the alpha subunit of AChR (AChRalpha) in the thymus, and advance a new hypothesis that examines the intrathymic expression of this autoantigen in disease pathogenesis.
Immunologic Research 02/2003; 27(2-3):399-408. · 2.96 Impact Factor