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Classification of Genetically Defined Autoinflammatory Diseases

  • Raphaela Goldbach-ManskyEmail author
  • Adriana A. de Jesus
Chapter

Abstract

Autoinflammatory diseases are hyperinflammatory, immune-dysregulatory conditions that typically present in early childhood with fever, rashes and disease-specific patterns of sterile organ inflammation of predominantly innate immune cells. The identification of disease-causing genetic mutations in key innate immune pathways that regulate pro-inflammatory cytokines, paired with the impressive clinical responses to cytokine blocking therapies has led to the concept that cytokine activation drives “cytokine amplification loops” that lead to the development of systemic and organ-specific disease manifestations of autoinflammatory diseases. While the initial discoveries of the genetic causes of autoinflammatory diseases and the clinical treatment successes centered around conditions that were presumed to be caused by interleukin (IL)-1 overproduction and signaling, more recent studies are providing insights into proinflammatory cytokine dysregulation, that includes Type-I interferon (IFN), IL-17, IL-18 or IL-36 and more generally ubiquitination disorders that affect nuclear factor kappa B (NF-kB) dysregulation. Characteristic clinical findings such as fever patterns, type of skin lesions and pattern of organ inflammation track with specific innate immune pathways. In this chapter we use two different classification systems of the known genetically-defined autoinflammatory diseases, a clinical classification system based on skin lesions, other characteristic clinical features and the pattern of the inflammatory episodes (i.e. fever pattern), and a pathophysiological classification based on innate immune sensor and cytokine pathways that are dysregulated. The clinical and pathophysiological classification systems can be integrated.

Keywords

Classification Autoinflammatory diseases Dermatologic manifestations Key inflammatory and regulatory pathways Interleukin (IL)-1 Type-I interferon (IFN) IL-18 IL-23/IL-12/IL-17 axis Tumor necrosis factor (TNF) Nuclear factor kappa B (NF-kB) 

Abbreviations

ACH

Acrodermatitis continua of Hallopeau

AGS

Aicardi-Goutières syndrome

AIM

Absent in melanoma

AISLE

Autoinflammatory syndrome associated with lymphedema

AMPS

AP1S3 mediated psoriasis

APLAID

PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation

ASC

Apoptosis related speck-like protein containing CARD

CAMPS

CARD14-mediated psoriasis

CANDLE

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures

CAPS

Cryopyrin-associated periodic syndromes

CARD

Caspase activation and recruitment domains

CINCA

Chronic infantile neurologic, cutaneous and articular syndrome

CTLs

Cytotoxic CD8+ T cells

DADA2

Deficiency of adenosine deaminase 2

DC

Dendritic cells

DIRA

Deficiency of the interleukin 1 receptor antagonist

DITRA

Deficiency of the interleukin 36 receptor antagonist

DUB

Deubiquitinases

FCAS

Familial cold autoinflammatory syndrome

FCAS2

Familial cold autoinflammatory syndrome 2

FDA

Food and Drug Administration

FKLC

Familial keratosis lichenoides chronica

FLH

Familial hemophagocytic lymphohistiocytosis

FMF

Familial Mediterranean fever

GOF

Gain-of-function

GPP

Generalized pustular psoriasis

HA20

Haploinsufficiency of A20

HIDS

Hyperimmunoglobulinemia D and periodic fever syndrome

HLH

Hemophagocytic lymphohistiocytosis

HSCT

Hematopoietic stem cell transplantation

IL

Interleukin

IL-1Ra

IL-1 receptor antagonist

IFN

Interferon

IRF

Interferon regulatory factor

IRS

IFN response gene signature

ISGF

Interferon stimulated gene factor

JAK

Janus kinase

JMP

Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy

LACC1

Laccase (multicopper oxidoreductase) domain-containing 1

LOF

Loss-of-function

LPS

Lipopolysaccharide

LRR

Leucine-rich repeat

LUBAC

Linear ubiquitination chain assembly complex

MAP

Mitogen-activated protein

MAS

Macrophage activation syndrome

MDA5

Melanoma differentiation-associated protein 5

MDFIC

MyoD family inhibitor domain containing

MKD

Mevalonate kinase deficiency

MPO

Myeloperoxidase

MSPC

Multiple self-healing palmoplantar carcinoma

MWS

Muckle-Wells syndrome

NAIAD

NLRP1-associated autoinflammation with arthritis and dyskeratosis

NAIP

NLR family apoptosis inhibitory protein

NDAS

NEMO deleted exon 5 autoinflammatory syndrome—X-linked

NEMO

NF-κB essential modulator

NF-κB

Nuclear factor kappa B

NISBD1

Neonatal inflammatory skin and bowel disease-1

NK

Natural killer

NLR

NOD-like receptor

NLRC

NOD-like receptor family CARD domain containing

NLRP

NOD-like receptor family pyrin domain containing

NOD

Nucleotide-binding oligomerization domain

NOMID

Neonatal-onset multisystem inflammatory disease

NSAIDs

Non-steroidal anti-inflammatory drugs

ORAS

Otulin-related autoinflammatory syndrome/Otulipenia

PAAND

Pyrin-associated autoinflammation with neutrophilic dermatosis

PAMP

Pathogen-associated molecular pattern

PAPA

Pyogenic arthritis, pyoderma gangrenosum and acne (syndrome)

PFIT

Periodic fever, immunodeficiency, and thrombocytopenia

PGA

Pediatric granulomatous arthritis

PLAID

PLCG2-associated antibody deficiency and immune dysregulation

PPP

Palmoplantar psoriasis

PRAAS

Proteasome-associated autoinflammatory syndrome

PRR

Pattern recognition receptors

PYD

Pyrin domain

RIG

Retinoic acid-inducible gene

RLR

RIG-like receptor

SAVI

STING-associated vasculopathy with onset in infancy

SCAN

Syndrome of enterocolitis and autoinflammation associated with mutation in NLRC4

SDH

Succinate dehydrogenase

SIFD

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

SIRS

Systemic inflammatory response syndrome

SMS

Singleton-Merten syndrome

SPENCD

Spondyloenchondrodysplasia with immune dysregulation

STAT

Signal transducer and activator of transcription

STING

Stimulator of IFN genes

TACE

TNF-α convertase enzyme

TNF

Tumor necrosis factor

TORCH

Toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex

TRAP

Tartrate-resistant phosphatase

TRAPS

TNF receptor-associated periodic syndrome

TRAPS11

TNFRSF11A-associated hereditary fever disease

TYK

Tyrosine kinase

USP

Ubiquitin-specific peptidase

VEOIBD

Very early-onset inflammatory bowel disease

XIAP

X-linked inhibitor of apoptosis

Supplementary material

420188_1_En_10_MOESM1_ESM.xlsx (33 kb)
Supplementary Data 1 Clinical features of Mendelian autoinflammatory diseases. Abbreviations: PRR pattern recognition receptors; IL interleukin; CAPS cryopyrin-associated periodic syndrome; FCAS familial cold autoinflammatory syndrome; MWS Muckle-Wells syndrome; NOMID neonatal-onset mutlisystem inflammatory disease; CINCA chronic infantile neurological cutaneous and articular syndrome; FMF familial Mediterranean fever; PAAND pyrin-associated autoinflammation with neutrophilic dermatosis; HIDS/MKD hyperimmunoglobulinemia D with periodic fever syndrome/mevalonate kinase deficiency; TRAPS tumor necrosis facor receptor-associated periodic syndrome; DIRA deficiency of the interleukin-1 receptor antagonist; SAVI STING-associated vasculopathy with onset in infancy; AGS Aicardi-Goutières syndrome; CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; SPENCDI spondyloenchondrodysplasia with immune dysregulation; CAMPS CARD14-mediated psoriasis; AMPS AP1S3 mediated psoriasis; DITRA deficiency of the IL-36 receptor antagonist; ORAS otulin-related autoinflammatory syndrome/otulipenia; NDAS NEMO deleted exon 5 autoinflammatory syndrome—X-linked; HA20 haploinsufficiency of A20; LACC1 laccase (multicopper oxidoreductase) domain-containing 1; MAS macrophage activation syndrome; FHL familial hemophagocytic lymphohistiocytosis; CHS Chediak-Higashi syndrome; PLAID PLCG2-associated antibody deficiency and immune dysregulation; APLAID PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation; PAPA pyogenic arthritis, pyoderma gangrenosum and acne syndrome; PFIT perioidc fever, immunodeficiency, and thrombocytopenia; DADA2 deficiency of adenosine deaminase 2; IBD inflammatory bowel disease; AR autosomal recessive; AD autosomal dominant; URI upper respiratory infection; AIHA autoimmune hemolytic anemia; AITP autoimmune thrombocytopenic purpura; ANA anti-nuclear antibody; IFN interferon; TNF tumor necrosis factor (XLSX 32 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Raphaela Goldbach-Mansky
    • 1
    Email author
  • Adriana A. de Jesus
    • 1
  1. 1.Translational Autoinflammatory Diseases SectionNational Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)BethesdaUSA

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