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PATHOGENESIS OF PEMPHIGUS
Introduction
Pemphigus antibodies Pemphigus antigens Role of genetic background Role of environnemental factors Mechanism of acantholysis
INTRODUCTION
Identification Correspondence with clinical types of pemphigus 3) Mechanisms of the tolerance breakdown
2) Antigens:
PATHOGENESIS OF PEMPHIGUS
Introduction
Pemphigus antibodies
Pemphigus antigens Role of genetic background Role of environnemental factors Mechanism of acantholysis
PATHOGENESIS OF PEMPHIGUS
Pemphigus antigens
Role of genetic background Role of environnemental factors Mechanism of acantholysis
easiest method can detect multiple antigens ONLY detect Ab directed against linear epitopes (Ag are denatured with detergents) (+++)
IMMUNOPRECIPITATION
Use radio labelled cultured keratinocytes extracts Use protein A to precipitate IgG antibodies Complex, time-consuming method Can detect Ab against conformational epitopes
- PNP Ab are deposited both on the extracellular area and the intrecellular plaques of desmosomes - And on the hemidesmosomes of the basement membrane zone
- PNP sera recognize an antigenic complex composed of proteins that belong to the plakin family
-Desmoplakin I : 250-kD -BPAG1 : 230-kD -Desmoplakin 2 and Envoplakin : 210-kD -Periplakin : 190-kD -Plectin : 600-kD -Unidentified : 170-kD
These findings explain the clinical and histological similarities between PV and PNP patients.
THIRD STEP : CLONING AND SEQUENCING GENES ENCODING FOR PEMPHIGUS ANTIGENS
Desmoglein 1 and 3 belong to cadherins a family of proteins involved in cell adhesion.
PATHOGENESIS OF PEMPHIGUS
PATHOGENESIS OF PEMPHIGUS
Patients : exclusive IgG4 Abx70 fold higher response than healthy individuals mainly directed against EC1 EC2
ENDEMIC PEMPHIGUS
Environnemental factors Insect-bite transmitted Infectious diseases ? Component of insect vector saliva insect bite Production of Anti DSG1 Ab (IgG1-2-3) EC5 Healthy individuals genetic factors HLA DR3-DR4-DR14
switch
PATHOGENESIS OF PEMPHIGUS
Introduction Pemphigus antibodies Pemphigus antigens Role of genetic background Role of environnemental factors
Mechanism of acantholysis
MECHANISM OF ACANTHOLYSIS
Exact mechanism IC Ab causes loss of cell adhesion : unclear. Hypothesis : 1) IgG could block adhesion sites of DSG. 2) The paratope of some anti-DSG Ab may contain adhesive sequences and interact with the adhesive function of DSG by mechanism of molecular mimicry.
MECHANISM OF ACANTHOLYSIS
Hypothesis : 3) IgG could stimulate the release of proteolystic enzymes. (SSSS is caused by a toxin that binds specifically DSG1 and cleaves it)
MECHANISM OF ACANTHOLYSIS
Hypothesis : 4) IC IG could trigger a signalling event via the intracellular signalling pathway (phosphokinase C) that : interfere with DSG function or structure inducing dissociation from plakoglobin, leading to disruption of desmosomes. reorganisation of the cytoskeleton of keratinocytes
CONCLUSION
Significant advances in the understanding of pemphigus pathogenesis New techniques facilitate the diagnosis and the evaluation of patients prognosis Use of recombinant Ag for targeting auto-reactive Bcells open a way for specific immunotherapy Understanding of genetic susceptibility and triggering factors of pemphigus will possibly provide opportunity to prevent and/or to use causative treatments in the future