This document discusses autoinflammatory disorders (AIDs), which are characterized by recurrent episodes of systemic inflammation in the absence of pathogens or autoantibodies. AIDs are caused by primary dysfunction of the innate immune system and are associated with mutations in genes regulating innate immunity like the NLR gene family. Specific AIDs discussed include familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, cryopyrin-associated periodic syndromes, and pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome. Autoinflammation results from dysregulation of the inflammasome complex and excessive interleukin-1 beta secretion.

1. By
M.Yousry Abdel-Mawla,MD
Professor of Dermatology,Zagazig Univesity,Egypt

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3.  Inflammation is defined as a series of protective
and regen-erative responses of the body.
 Host defense system of the skin is composed of
a barrier, innate immunity and acquired
immunity.
 Three layers of the protection drive the most
suitable re-sponse against infectious agents and
external dangers whereas the basic response at
the transcriptional level in the cell is very limited.
 Disorder of the specific layer of the host defense
system of the skin can induce an inflammatory
skin disease, which partly simulates the actual
protective response against infec-tions and
dangers
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5.  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.M.Y.ABDEL-MAWLA 5

6.  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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9.  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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11.  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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12.  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-recruiting
domain (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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14.  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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15.  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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18.  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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21. Autoinflammatory disorders
(AIDS) are characterized by
recurrent episodes of systemic
inflammation in the absence of
pathogens, autoantibodies or
antigen specific T cells.
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22. 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.
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23. 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.
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28. 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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29. -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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30. - 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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32.  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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33.  Mutations in the TNFRSF1A (tumor necrosis
factor receptor superfamily, member 1A)
gene coding for a TNF receptor.
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34. - 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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36.  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 plaques
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 cases
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37.  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.

40. They are 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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41. -Autosomal dominant disease.
-Early onset cold-induced itchy urticarial rash
- Chills, fever, arthralgia, mialgia, headache
and conjunctivitis.
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42. -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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43. -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.

46. - 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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47. 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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48. 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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50. Behcet's disease .
Crohn's disease.
Sarcoidosis.
Psoriatic arthritis.
Atopic dermatitis.
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54.  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-Nneonatal onset multisystem inflammatory
disorder.
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55.  Evanescent, nonpruritic, urticaria-like Papules
and confluent geographic plaques on the
trunk and extremities, periodic fevers, and distal
Arthralgia.
 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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58.  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-threonine
phosphatase interacting protein 1), also known
as
CD2BP1, cause increased binding of the
protein
pyrin to the pyrin domain of NLRP, leading to
inflammasome formation.
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59.  Laboratory findings include elevated IL-1ß,
tumor necrosis factor (TNF)-alfa, CRP, and
ESR, as well as hypogammaglobulinemia
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61.  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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63. 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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64.  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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65.  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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66.  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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68.  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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