The Systemic Autoinflammatory Diseases Inborn Errors of the Innate Immune System

Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA [email protected]

1 Introduction 128

2 Familial Mediterranean Fever 130

3 Syndrome of Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne ... 133

4 The Cryopyrinopathies:

Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, and Neonatal-Onset Multisystem Inflammatory Disease 135

5 Blau Syndrome 139

6 TNF Receptor-Associated Periodic Syndrome 141

7 Hyperimmunoglobulinemia D with Periodic Fever Syndrome 145

8 Concluding Remarks 148

References 149

Abstract The autoinflammatory syndromes are a newly recognized group of immune disorders that lack the high titers of self-reactive antibodies and T cells characteristic of classic autoimmune disease. Nevertheless, patients with these illnesses experience unprovoked inflammatory disease in the absence of underlying infection. Here we discuss recent advances in eight Mendelian autoinflammatory diseases. The causative genes and the proteins they encode play a critical role in the regulation of innate immunity. Both pyrin and cryopyrin, the proteins mutated in familial Mediterranean fever and the cryopyrinopathies, respectively, are involved in regulation of the pro-inflammatory cytokine, IL-1 p, and may influence the activity of the transcription factor, NFkB. NOD2, the Blau syndrome protein, shares certain domains with cryopyrin and appears to be a sensor of intracellular bacteria. PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses. Somewhat unexpectedly, mutations in the p55 TNF receptor lead not to immunodeficiency but to dramatic inflammatory disease, the mechanisms of which are still under investigation. Finally, the discovery of the genetic basis of the hyper-immunoglobulinemia D with periodic fever syndrome has provided a fascinating but incompletely understood link between cholesterol biosynthesis and autoinflammation. In this manuscript, we summarize the current state of the art with regard to the diagnosis, pathogenesis, and treatment of these inborn errors of the innate immune system.

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