AUTOINFLAMMATOR

Y DISEASES
(SYNDROMES)
DR MOHAMMED ELBEHEIRY
OVERVIEW

• Incidence/ prevalence: rare

• Inheritance: monogenic (i.e due to a defect in a single gene)
• Pathogenesis: abnormal activation in the innate immune system. Marks of autoimmunity
are absent.
CLINICAL FEATURES

1. Typically present in early childhood

2. Recurrent episodes seemingly unprovoked of fever (in most cases), multiorgan inflammation (frequently involving the skin,
joints, eyes and serous membranes).
3. The cutaneous findings vary and include:
o Transient maculo-popular/ urticarial eruptions
o Edematous plaques
o Sterile pustules
o Ulcerations
o Livedo reticularis
o Pernio like lesions
o Erysipelas like lesions
HISTOPATHOLOGY

the cutaneous infiltrates of autoinflammatory syndromes are variable:

1. Sterile pustules within the epidermis
2. Sterile neutrophils within the dermis: perivascular and interstitial infiltrates of
neutrophils within the dermis without vasculitis or significant edema
3. Granulomas within the dermis
DIAGNOSIS

• Clinical presentation
• Histopathology
• Elevated acute phase reactants, neutrophils, CRP, serum amyloid A
• Genetic Diagnosis
• Other investigations will depend on the specific disorder. E.g. hearing tests in
cryopyrinopathies
ROLE OF INNATE IMMUNITY IN INFLAMMATION

• Inflammation is a protective response by the host aiming to remove harmful stimuli and
to develop healing process to repair damaged tissue
• The innate immune system is the first line of defense against cellular and microbial
insults. It uses pattern recognition receptors PRR to detect
1. Pathogen associated molecular patterns PAMPs
2. Damage associated molecular patterns DAMPs: self derived molecules from damaged
cells
• PRR include:
1. Toll like receptors TLR: membrane bound receptors
2. Nod like receptors NLR: intracellular receptors
NOD LIKE RECEPTORS

• Human NLRs are subclassified into 5 sub families: NLRA, NLRB, NLRC, NLRP, NLRX
• All 22 human NLRs contain 3 main domains:
1.Central domain: called the nucleotide binding domain NBD
2.C terminal domain: ligand sensing leucine rich repeats LRR. It is present in all NLRs
except NLRP10
3.N terminal domain: responsible for all the functional properties to the NLR. The different
NLRs subfamilies differ greatly at their N terminal
NLR sub family N terminal domain Example
NLRC One or more caspase recruitment NLRC4
domains CARD
NLRP Pyrine domains PYD NLRP3
FORMATION OF THE INFLAMMASOME

• Upon activation, some NRLs form multi-protein complexes termed inflammasomes.

Inflammasomes are consisting of:
1. A nucleotide binding domain NRL
2. An adaptor protein= apoptosis associated speck like protein containing a CARD
domain ASC. ASC has two domains a pyrin domain PYD and a CARD domain. This
enables it to bridge interactions between NLRPs and pro-caspase 1.
3. The effector protein, pro-caspase 1 which contains CARD domain in its N-terminus.
• Pro-caspase 1, a protease, undergoes cleavage to form the activated form of caspase-1.
Caspase-1 cleaves both pro- IL-1b and pro- IL- 18 into their mature and secreted forms.
IL-1b and IL-18 are both potent pro-inflammatory cytokines, with a wide variety of
effects on the innate and adaptive immune systems.
PATHOPHYSIOLOGY

• The innate immune response is programmed for immediate action resulting in massive
and self-maintaining inflammation that can be harmful to the host.
• Most of the auto-inflammatory disorders are characterized by interleukin-1 over-activity
whether
1. Excessive production of IL-1
2. Defensive inhibition of IL-1
TREATMENT

Anti-IL-1 therapy, including:

• IL-1 receptor antagonist anakinra
• IL-1 trap rilonacept
• Anti- IL-1B: monoclonal antibody canakinumab