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T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens

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Abstract

Special populations of T helper cells drive B cells to produce IgG class switched, pathogenic autoantibodies in lupus. The major source of antigenic determinants (epitopes) that trigger interactions between lupus T and B cells is nucleosomes of apoptotic cells. These epitopes can be used for antigen-specific therapy of lupus. Secondly, the autoimmune T cells of lupus are sustained because they resist anergy and activation-induced programmed cell death by markedly upregulating cyclooxygenase (COX) 2 along with the antiapoptotic molecule c-FLIP. Only certain COX-2 inhibitors block pathogenic anti-DNA autoantibody production in lupus by causing death of autoimmune T helper cells. Hence COX-2 inhibitors may work independently of their ability to block the enzymatic function of COX-2, and structural peculiarities of these select inhibitors may lead to better drug discovery and design.

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Abbreviations

APC :

Antigen-presenting cell

Cbl :

Cassitus B lymphoma oncogene

CD40L :

CD40 ligand

c-FLIP :

Cellular Fas-associated death domain-like interleukin 1β converting enzyme inhibitory protein

COX :

Cyclooxygenase

DC :

Dendritic cell

ERK :

Extracellular signal regulated kinase

FADD :

Fas-associated death domain

FasL :

Fas ligand

IAP :

Inhibitor of apoptosis protein

IL :

Interleukin

PG :

Prostaglandin

SLE :

Systemic lupus erythematosus

TCR :

T cell receptor

Th :

T helper

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Acknowledgements

These studies were supported by National Institutes of Health grants R37-AR39157 and RO1-AI41985 to S.K.D.

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  1. Departments of Medicine and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 240 East Huron St., Chicago, IL, 60611, USA

    Syamal K. Datta, Li Zhang & Luting Xu

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  1. Syamal K. Datta
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Correspondence to Syamal K. Datta.

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Datta, S.K., Zhang, L. & Xu, L. T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens. J Mol Med 83, 267–278 (2005). https://doi.org/10.1007/s00109-004-0624-2

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