Conférence de Pr Mohamed Ridha Barbouche lors du Colloque Jeunes Chercheurs de l'IPT (8-9 décembre 2016)
Background: PIDs are a heterogeneous group of inherited disorders in which immune system dysfunctions
cause an enhanced susceptibility to infections that is the common clinical feature of these diseases. To date,
more than 250 genes have been identified and associated with as many different immunodeficiencies. The
frequency of PIDs is higher in North-Africa and Middle-East as compared to Europe and North-America.
Indeed, our population is characterized by a high frequency of consanguineous marriages which may reach
50% in rural areas. This may account for the higher incidence of autosomal recessive immunodeficiencies
observed.
Material and Methods: During the last twenty years, we’ve diagnosed and investigated at the Institut Pasteur
de Tunis one thousand cases of PIDs including patients with combined immunodeficiencies, antibody
deficiencies, phagocytosis defects, complement deficiencies and other well-defined immunodeficiencies.
Results: The immuno-genetic investigation and the establishment of an accurate diagnosis allowed an
appropiate and targeted treatment of the affected children e.g. bone marrow transplantation, substitutive
intravenous immunoglobulins, IFNg or GM-CSF therapy... This did also allow us to establish a preventive
approach by genetic counselling and prenatal diagnosis. Moreover, we did contribute to dissection of the
IFNg-IL12/23 dependant pathway in patients with mendelian susceptibility to mycobacterial diseases, which
might be a model to better understand immune responses during tuberculosis. We did also contribute to
the World Health Organization efforts to eradicate poliomyelitis by studying PIDs patients who can be
directly or indirectly infected by oral vaccine strains and may become chronic excretors of polioviruses.
This is a major concern since long-lasting strains in the intestine of these patients have been shown to
be able to revert and cause vaccine-derived poliomyelitis outbreaks, representing a potential reservoir
for infection in the post eradication era. Furthermore, wecontributed to better understand the role of
TH17 cells in susceptibility to severe fungal diseases and we discovered, recently, a novel gene underlying
susceptibility to staphylococcal infection, inflammation and allergy in hyper-IgE syndrome patients.
Conclusion: The study of these diseases helps unravelling specific immunological pathways, rare
autosomal forms offer a privileged physiopathological model for infections including some which are
linked to global health challenges
Science Ensemble : La boutique des Sciences de l'Institut Pasteur de Tunis
Déficits immunitaires primitifs (DIP) : modèle pour l'étude de la susceptibilité génétique aux infections
1. Institut Pasteur de Tunis
Primary immunodeficiencies: a model for the study
of genetic susceptibility to infections in humans.
Mohamed Ridha BARBOUCHE M.D., Ph.D.
Department of Immunology, Institut Pasteur de Tunis,
Tunisia
CJC, 7th-9th December 2016
2. Institut Pasteur de Tunis
Qu’est-ce que les Déficits Immunitaires Primitifs?
• Les Déficits Immunitaires Primitifs (DIPs) sont un groupe hétérogène de
maladies dans lesquelles un défaut génétique du système immunitaire est
responsable notamment d’une susceptibilité accrue aux infections.
• Les DIPs touchent essentiellement les enfants en bas âge avec survenue
d’infections qui sont récurrentes, sévères et rebelles au traitement
habituel. Elles sont parfois de type opportunistes.
• La suspicion du diagnostic de DIP est clinique et sa confirmation est
biologique.
3. Institut Pasteur de Tunis
Pourquoi cette pathologie?
• Les infections récurrentes fragilisent de façon sévère et durable la santé de
l’enfant et peuvent engager le pronostic vital.
• La consanguinité qui caractérise la population tunisienne est responsable d’une
fréquence accrue des DIPs dans notre pays.
• La compréhension de la physiopathologie de ces maladies est l’une des clés du
succès du suivi médical et de la prévention.
4. Institut Pasteur de Tunis
Bittles and Black PNAS; 2010
MHC class II deficiency
IFN-γ receptor 1 deficiency
3MC syndrome COLEC11 and MASP1
deficiency
MHC class II deficiency
IFN-γ receptor 1 deficiency
3MC syndrome COLEC11 and MASP1
deficiency
MHC class II deficiency
Griscelli syndrome, type2
Epidermo- dysplasia verruciformis
MHC class II deficiency
Griscelli syndrome, type2
Epidermo- dysplasia verruciformis
MHC class II deficiency
MHC class I deficiency
Griscelli syndrome, type2
Familial hemophagocytic lymphohistiocytosis (FHL)
syndromes
IL12 and IL23 receptor β1 chain deficiency
Chronic mucocutaneous candidiasis (CMC)
MHC class II deficiency
MHC class I deficiency
Griscelli syndrome, type2
Familial hemophagocytic lymphohistiocytosis (FHL)
syndromes
IL12 and IL23 receptor β1 chain deficiency
Chronic mucocutaneous candidiasis (CMC)
DOCK8 deficiency
Hepatic venoocclusive Disease with
ID(VODI)
Early onset inflam. bowel disease/IL10R
DOCK8 deficiency
Hepatic venoocclusive Disease with
ID(VODI)
Early onset inflam. bowel disease/IL10R
Majeed syndrome/LPIN2Majeed syndrome/LPIN2
Leukocyte adhesion deficiency type 2
(LAD2)
Leukocyte adhesion deficiency type 2
(LAD2)
CD45 deficiency
NHEJ1 deficiency
ITK deficiency
µ heavy chain deficiency
Igα deficiency
CD19 deficiency
Syntaxin 11 deficiency, FHL4
STXBP2 (Munc 18-2) deficiency, FHL5
G6PC3
Leukocyte adhesion deficiency type 3
(LAD3)
Papillon– Lefèvre syndrome
MyD88 deficiency
C1q deficiency
MASP1 deficiency
CD45 deficiency
NHEJ1 deficiency
ITK deficiency
µ heavy chain deficiency
Igα deficiency
CD19 deficiency
Syntaxin 11 deficiency, FHL4
STXBP2 (Munc 18-2) deficiency, FHL5
G6PC3
Leukocyte adhesion deficiency type 3
(LAD3)
Papillon– Lefèvre syndrome
MyD88 deficiency
C1q deficiency
MASP1 deficiency
CD40 deficiency
Dyskeratosis congenita (AR-DKC)
UNC13D (Munc13-4) deficiency, FHL3
STXBP2 (Munc 18-2) deficiency, FHL5
IRAK4 deficiency
3MC syndrome COLEC11 and MASP1
deficiency
CD40 deficiency
Dyskeratosis congenita (AR-DKC)
UNC13D (Munc13-4) deficiency, FHL3
STXBP2 (Munc 18-2) deficiency, FHL5
IRAK4 deficiency
3MC syndrome COLEC11 and MASP1
deficiency
DOCK8 deficiencyDOCK8 deficiency
AR-HIES/DOCK8
Kostmann disease/HAX1
Predisposition to fungal diseases /CARD9
AR-HIES/DOCK8
Kostmann disease/HAX1
Predisposition to fungal diseases /CARD9
3MC syndrome COLEC11 and
MASP1 deficiency
3MC syndrome COLEC11 and
MASP1 deficiency
3MC syndrome COLEC11 and
MASP1 deficiency
3MC syndrome COLEC11 and
MASP1 deficiency
UNC13D (Munc13-4) deficiency, FHL3
FADD deficiency
IL12p40 deficiency
UNC13D (Munc13-4) deficiency, FHL3
FADD deficiency
IL12p40 deficiency
5. Institut Pasteur de Tunis
Pourquoi maintenant et ici?
• Cette pathologie semble plus fréquente dans les populations hautement
consanguines mais reste largement sous-diagnostiquée dans certaines régions
du pays.
• Le laboratoire de l’Institut Pasteur de Tunis a acquis une expertise dans le
diagnostic biologique des DIPs et dispose d’un personnel qualifié.
• Un réseau de pédiatres et d’immunologistes capables d’investiguer et prendre
en charge les patients existe mais doit être renforcé.
• Des structures hospitalières et des ONG sont prêtes à s’investir dans
l’amélioration de la prise en charge des patients et assurer sa réussite.
6. Institut Pasteur de Tunis
Reported incidence of PIDs in Tunisia
J Clin Immunol 2015
7. Institut Pasteur de Tunis
Quels sont nos objectifs?
• Aider les cliniciens à porter un diagnostic précis et mettre en œuvre un
traitement adapté et une approche préventive appropriée.
• Renforcer les capacités du laboratoire de référence à l’IPT dans l’investigation
spécialisée avec l’introduction des examens appropriés et nécessaires au
diagnostic et au suivi de ces patients, ainsi que la mise en place d’un conseil
génétique.
• Mieux comprendre la physiopathologie de ces maladies, leurs bases
moléculaires et identifier de nouveaux gènes et voies métaboliques impliquées
dans les réponses immunes vis-à-vis de différents pathogènes.
• Impliquer les organisations non gouvernementales dont les associations de
parents de malades dans la sensibilisation et le soutien aux familles affectées,
particulièrement les mamans.
• Réduire les coûts médicaux et sociaux de ces maladies chroniques de l’enfant.
8. Institut Pasteur de Tunis
Le cadre logique:
• Objectif général et Objectifs spécifiques
• Actions à développer
• Résultats attendus
• Indicateurs et moyens de vérification
28. Institut Pasteur de Tunis
Families pedigrees and PGM3 gene
identification
A novel Congenital Disorder of Glycosylation due to biallelic
hypomorphic mutations of PGM3 gene, leading to inborn errors of
development and immunity.
J. Allergy Clin. Immunol. 2014;133:1410-9.
29. Institut Pasteur de Tunis
Glucose
Hexosamine
Pathway
GlcNAc-6-P
PPi
GlcNAc-1-P
UDP-GlcNAc
PGM
3
UTP
pyrophosphsphorylas
e
In neutrophils
In EBV cell lines
30. Institut Pasteur de Tunis
Expression
N-glycosylated at 9 of 11 potential
glycosylation sites
Present in all type of cells
Regulation of hematopoiesis,
inflammation, and neural survival.
gp130-dependent IL-6 signaling pathway
31. Institut Pasteur de Tunis
PGM3 mutations
Catalytic
domain
Mg binding
domain
Sugar binding
domain
PO binding
domain
Leu83Ser
Family B
Glu340del
Family A
32. Institut Pasteur de Tunis
The American Journal of Human Genetics 95, 1–12, July 3, 2014
34. Institut Pasteur de Tunis
In Summary:
The study of these diseases helps unravelling
specific immunological pathways.
Rare autosomal forms offer a privileged
physiopathological model for infections including
some which are linked to global health challenges.
Tanslational research in PIDs with the
development of novel therapeutic approaches and
the improvement of health care is a major objective.
35. Institut Pasteur de Tunis
• Imen Ben-Mustapha
• Najla Mekki
• Meriam Ben Ali
• Hanen Ouadani
• Khaoula Ben Farhat
• Nourhen Agrebi
• Leila Ben Khemis
• Houda Elloumi
• Atfa Sassi
• Beya Larguèche
• Mohamed Béjaoui
• Mongia Hachicha
• Jean-Laurent Casanova
• François Rougeon
• Bodo Grimbacher
Thanks to patients and their families.
Contributors: