Periodic fever syndromes and other autoinflammatory diseases: An overview
- Peter A Nigrovic, MD
Peter A Nigrovic, MD
- Associate Professor of Medicine
- Harvard Medical School
- Section Editors
- E Richard Stiehm, MD
E Richard Stiehm, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Immunology and Immunodeficiency
- Distinguished Research Professor of Pediatrics
- David Geffen School of Medicine at UCLA
- Sheldon L Kaplan, MD
Sheldon L Kaplan, MD
- Editor-in-Chief — Pediatrics
- Section Editor — Pediatric Infectious Diseases
- Professor and Vice Chairman for Clinical Affairs
- Baylor College of Medicine
In the autoinflammatory diseases, pathogenic inflammation arises through aberrant, antigen-independent activation of the immune system. Many of these diseases present with recurrent fevers and are termed the periodic fever syndromes, although other features may sometimes dominate the clinical picture. The best characterized autoinflammatory diseases arise from mutations in single genes, but related mechanisms participate in many diseases in which inflammation contributes to tissue injury.
An overview of autoinflammatory diseases is presented here, with a focus on shared pathogenic and pathophysiologic mechanisms. While the most salient features of the individual disorders are discussed in this topic review, more detailed descriptions of the clinical manifestations, diagnosis, and treatment of the major autoinflammatory diseases are presented elsewhere. (See appropriate topic reviews.)
OVERVIEW OF PATHOGENESIS
Immune defense requires both antigen-specific and antigen-independent mechanisms. The antigen-specific arm of the immune response, referred to as adaptive immunity, is based upon learned self/nonself discrimination mediated by selective expansion of T- and B-cell clones in which genetic recombination has generated antigen-specific receptors. (See "The adaptive cellular immune response".)
However, these "learned" responses are not the only mechanism of immune defense. Innate immunity refers to a network of cells and proteins that respond to infection or tissue injury through genetically "hard-wired" recognition of foreign molecules (eg, bacterial cell wall components) or host molecules produced or released by damaged cells (eg, interleukin-1 [IL-1] and uric acid crystals). Neutrophils, macrophages, mast cells, and natural killer cells are among the principal cellular effectors of innate immunity. Complement, a set of proteins that recognize and bind nonself targets, exemplifies noncellular innate immunity. (See "An overview of the innate immune system" and "Complement pathways" and "Toll-like receptors: Roles in disease and therapy".)
Innate and adaptive immune mechanisms work closely together. Recognition of danger signals by innate immune mechanisms directs the development of adaptive immune responses, while lack of such recognition favors tolerance. Established adaptive immune responses recruit innate immunity to assist with the effector response. As examples, T cells can recruit neutrophils, and B-cell-derived antibodies can target bacteria for lysis by complement.
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- OVERVIEW OF PATHOGENESIS
- HALLMARKS OF THE AUTOINFLAMMATORY DISEASES
- DIFFERENTIAL DIAGNOSIS
- MAJOR PERIODIC FEVER SYNDROMES
- Familial Mediterranean fever
- TNF receptor-1 associated periodic syndrome
- Hyperimmunoglobulin D syndrome
- Cryopyrin-associated periodic syndromes
- PFAPA syndrome
- OTHER AUTOINFLAMMATORY DISORDERS
- Deficiency of the interleukin-1 receptor antagonist
- PAPA syndrome
- Blau syndrome
- Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature
- Deficiency of the interleukin-36 receptor antagonist
- Chronic recurrent multifocal osteomyelitis
- STING-associated vasculopathy with onset in infancy
- NLRC4-activating mutations
- LUBAC deficiency