ByM.Yousry Abdel-Mawla,MD

Professor of Dermatology,Zagazig Univesity,Egypt

Autoinflammation(AID) is characterized by aberrant regulation of the innate immune system and often manifests as periodic fevers and systemic inflammation involving multiple organs, including the skin.

Mutations leading to abnormal behavior or activity of the interleukin 1 beta (IL-1ß)-processing inflammasome complex have been found in several autoinflammatory syndromes, for which anticytokine therapy such as IL-1 or tumor necrosis factor-alfa inhibition may be effective.

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AIDs have been classified as hereditary monogenic disorders

Ttransmitted with recessive or dominant inheritance and multifactorial polygenic diseases.

Genes associated with AIDs encode for

proteins of the inflammasome

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These two types of diseases, AIDs and autoimmune diseases (ADs), share some characteristics.

They start with the prefix “auto” to define a pathological process directed against self.

They are systemic diseases, frequently involving skin and musculoskeletal system.

They include monogenic and polygenic diseases.

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Both infectious and noninfectious stimuli are capable of triggering innate immune responses through membrane-bound pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or cytosolic PRRs such NLRs*(Nucleotide binding domain leucine rich (NLR)..

Binding of TLRs to pathogen- or danger-associated molecular patterns activates expression of inflammatory cytokines via nuclear gene transcription factors

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A family of genes known as the nucleotide binding domain leucine-rich repeat-containing

(NLR) genes are integral to autoinflammation

22 human NLR genes have been identified

Most NLRs include a caspase-recruitingdomain (CARD) or a pyrin domain at the N-terminal, a central nucleotide-binding domain (NACHT ), and a C-terminal leucine-rich repeat domain.

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NLRconsists of a nucleotide-binding domain (NBD) and leucine-rich repeats (LRRs).

NLR proteins have a central NBD (also known as NOD for nucleotide oligomerization domain) and, like the cell-surface Toll-like receptor domain-domain interactions.

The NLR family is further divided based on the variable N-terminal domain. NLRC proteins are an NLR subset with N-terminal caspase activation and recruitment domains (CARDs), whereas NLRP proteins, including the CAPS protein (cryopyrin/NLRP3), contain a novel death domain family motif known as the pyrin domain (PYD).

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The NLR proteins are thought to function as innate immunesensors of intracellular pathogens that escape the extracellular or membrane-associated TLR armament.

Inflammasomes have been implicated in the host response to various Gram-negative and Gram-positive bacteria.

Recruitment domains (CARDs) function is the activation of caspases.

NLR-related inflammasome complexes activate caspase-1, also known as the IL-1-converting enzyme.

The inflammasome is a master regulator of inflammation,translating a variety of microbe- and host-derived distress signals into IL-1_ activation

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IL-1b activation disorders inflammasomopathies).

Nuclear factor (NF)- kappaB (NF-kB) activation syndromes.

Protein misfolding disorders.

Complement regulatory diseases.

Disturbances of cytokine signalling

Macrophage activation syndromes

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The autoinflammatory disorders

(AIDS) are a new and expanding

classification of inflammatory diseases

characterized by recurrent episodes of

systemic inflammation in the absence

of pathogens, autoantibodies or

antigen specific T cells.

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Autoinflammatory disorders are

caused by primary dysfunction of the

innate immune system, without

evidence of adaptive immune

dysregulation.

These disorders are all caused by

or associated with mutation of gene

regulating innate immunity.M.Y.ABDEL-MAWLA 18

Proteins that are mutated in AIDs

mediate the regulation of NF

kappa-B activation, cell apoptosis,

and IL-1beta secretion through

cross-regulated and sometimes

common signaling pathways.M.Y.ABDEL-MAWLA 19

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It characterized by periodic or recurrent episodes of systemic inflammation causing fever often associated with rash, serositis (peritonitis, pleuritis), lymphadenopathy, arthritis, and other clinical manifestations.

Systemic reactive (AA) amyloidosis may be a severe long-term complication.

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-Autosomal recessive.-Result from defective in pyrin protein that

down regulates inflammation. -Recurrent painful febrile attacks, peritonitis,

pleuritis, arthritis.-Skin rash: Eerysiplas like lesion .

Polyarteritis nodosa.Henoch-schonlein purpura.

-Histopathology :Massive neutrophilic infiltration in dermis.

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- Caused by a defective membrane receptor for TNF

- Fever, myalgia, arthralgia ,bdominal pain,

cojunctivitis.

- Skin rash :

-Migratory erythematous patch overlying the

area with myalgia.

-Urticarial like plaques

-Reccurent panniculitis.

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A dominantly inherited disorder

With prolonged periodic fevers (typically 7-21

days),

Erysipelas-like macules and patches overlying focal myalgia,

Abdominal pain, conjunctivitis, unilateral periorbital edema, and occasional lymphadenopathy

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Mutations in the TNFRSF1A (tumor necrosis factor receptor superfamily, member 1A) gene coding for a TNF receptor.

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- Autosomal recessive .

- Geneticaly conferred to deficiency of mevalonte kinase.

- Fever, severe abdominal pain, diarrhea ,arthritis, cervical lymphadenopathy.

- Skin rash:

- Macules ,papules ,nodules, petechiae, purpra.

- Sweet syndrome like .

- Cellulitis like

- Erythema elevatum diutinum.

- Elevated Ig D serum

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An autosomal recessive disorder

Characterized by periodic fevers, arthralgia, gastrointestinal disturbances, lymphadenopathy, and splenomegaly.

Skin findings range from intermittent painful, ill-defined erythematous macules and papules to edematous, erythematous plaquesm with prominent borders and occasionally central clearing.

Common areas of involvement are the trunk and extremities but can extend to the face, neck, and buttocks.

Amyloidosis can be present in severe casesM.Y.ABDEL-MAWLA 30

Histopathology:perivascular deposition of IgD and C3 complexes.

Elevation of serum IgD, whereas IgA elevation is variable

Mutations in the MVK (mevalonate kinase) gene, codesing for the enzyme mevalonate kinase, disrupt cholesterol synthesis, resulting in decreased serum cholesterol levels and an episodic increase in urinary mevalonic acid.

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They are a group of conditions, characterized

by a chronic or recurrent systemic inflammation

variably associated with a number of clinical

features, such as urticarial-like rash, arthritis,

sensorineural deafness, and central nervous

system and bone involvement.

Theyare associated with mutations of the

gene encoding cryopyrin →

hyperactivation of inflammasome → ↑

caspase-1 generation → hyperactivation

of IL-1 . Also activation of IL-6 is

mediated via NF kappa B.

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-Autosomal dominant disease.

-Early onset cold-induced itchy urticarial rash

- Chills, fever, arthralgia, mialgia, headache

and conjunctivitis.

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-Urticarial-deafness-amyloidosis syndrome(UDA).

- Famalial urticaria during early childhood .

- Characterised by periodic attacks of fever ,limb pain ,urticarial like eruption progressive perceptive deafness .

-May be associated with amayloid nephropathy.

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-Neonatal Onset Multisystem Inflammatory Disease (NOMID).

-Skin rash, severe arthritis ,chronic meningitis

leading to neurological damage.

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These disorders are dominated by

the presence of sterile pyogenic

abscesses affecting the skin,

joints, and bones.

- Caused by alteration of the protein PSTPIP_1

(proline, serine ,threonine, phosphatase, and

interactive protein).

- Mutation in its encoding gene →

hyperphosphorylated products → bind more to

pyrin → reduces pyrin’s braking on inflammasome

activation.

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1- pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome.

2- Chronic recurrent multifocal osteomyelitis (CRMO).

3- Majeed syndrome :

-CRMO

-Neutrophilic dermatosis.

-Sweet syndrome.

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Blau’s syndrome :

-Autosomal dominant disorder .

- it is characterized by familial

granulomatous arthritis, iritis, and skin

granulomas, (sarcoidosis and granuloma

annulare ).

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Behcet's disease .

Crohn's disease.

Sarcoidosis.

Psoriatic arthritis.

Atopic dermatitis.

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A rare childhood-onset disorder that presents with a wide spectrum of severity.

CAPS encompasses 3 distinct phenotypes, listed in the order ofincreasing severity:

1-familial cold autoinflammatory

2-syndrome, Muckle-Wells syndrome,

3-neonatal onset multisystem inflammatory disorder.

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Evanescent, nonpruritic, urticaria-like Papules and confluent geographic plaques on thetrunk and extremities, periodic fevers, and distalArthralgia.

Skin histology reveals a interstitial, perivascular, or perieccrine neutrophilic infiltrate.

Less common features: conjunctivitis, episcleritis, and uveitis, and neurologic manifestations:

headaches, sensorineural hearing loss, and chronic meningitis.

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A dominantly inherited disorder characterized by pyoderma gangrenosum( PG), acne vulgaris, and pyogenic arthritis.

PG lesions are characterized as single or multiple deep, ‘‘beefy red’’ ulcers with bluish, undermined borders.

Common locations are the legs and face and occasionally the intertriginous regions.

Mutations in PSTPIP1 (proline-serine-threoninephosphatase interacting protein 1), also known

asCD2BP1, cause increased binding of the

proteinpyrin to the pyrin domain of NLRP, leading to

inflammasome formation.

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Laboratory findings include elevated IL-1ß, tumor necrosis factor (TNF)-alfa, CRP, and ESR, as well as hypogammaglobulinemia

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Characterized by generalized annular erythematous/violaceous plaques, edematous eyelids, progressive facial lipodystrophy, arthralgia, early onset periodic fevers, and delayed physical development.

Homozygous and heterozygous mutations in the PSMB8 (proteasome subunit ß type 8) gene.

Skin histology typically : mature neutrophils and perivascular/ infiltrates rich in myeloid cells

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Abnormal innate immunity can be found in common dermatoses, including:atopic dermatitis, contact dermatitis, psoriasis, PG, neutrophilic dermatoses, acne, alopecia areata, vitiligo, and systemic lupus erythematosus (SLE).

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Atopic dermatitis involves complex interactions among environmental triggers (eg, S. aureus),

disruption of the epidermal barrier, IgE dysregulation, and genetic factors, including single nucleotide polymorphisms (SNPs) and de novo mutations in the NOD1, NLR, and CARD15 genes

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the house dust mite allergen Dermatophagoides pteronyssinus has been shown to stimulate secretion of IL-1ß and IL-18 from human keratinocytes.

Contact sensitizers can also activate the IL-1ß-processing inflammasomes in the hypersensitive reaction of contact dermatitis

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A role of innate immunity in psoriasis has been suggested by increased expression of pattern recognition receptor PRRs (eg, Toll-like receptor TLR-2, TLR-4, dectin-1) in patients with psoriasis compared with nonpsoriatic control subjects.

Neutrophil migration is observed in common inflammatory keratoses represented by psoriasis.

Abnormal regulation of the innate immune response and Th17 cell differentiation via IL-1 signaling may be associated with the molecular pathogenesis of psoriasis

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Autoinflammatory diseases were initially assigned to the hereditary recurrent fevers that are characterized by unprovoked episodes of inflammation without antigen-specific T cells or high titers of auto-antibodies, in contrast to the autoimmune diseases in which acquired immunity played an essential role.

Except for Blau syndrome and early-onset sarcoidosis that are associated with granuloma due to NOD2 mutations and classified as NF-κB activation disorders.

The major types of autoinflammatory diseases are defined as IL-1β activating disorders or inflammasomopathies.

This is based on accumulating evidence for the efficacy of anti-IL-1 therapy.

These diseases includeintrinsic cryopyrin-associated periodic syndrome (CAPS), extrinsic familial Mediterranean fever, hyper IgD syndrome, pyogenic sterile arthritis pyoderma gangrenosum andacne syndrome, and deficiency of an IL-1 receptor antagonist.

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