Hyper IgM Syndromes ANN DURANDY. B lymphocyte differentiation. T:B cell cooperation in germinal centres

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1 lymphocyte differentiation Hyper Syndromes ANN DURANDY Hematopoietic stem cell Myeloid precursor Lymphoid precursor NK one marrow D19 mmature gd D19 Memory cell Th D27 D19 + gg ga Mature Plasma cell Secondary lymphoid organ T: cell cooperation in germinal centres D40L D40 TRMH SR L-R gg, ga, S µ δ S γ3 S ε S µ δ S γ3 S S ε S µ δ S γ3 S S ε Error prone S S ε : T follicular helper, TR: T cell receptor, MH : major histocompatibility complex class, D40L: D40 Ligand, L-R: interleukine receptor, SR: g class switch recombination, : Antibody maturation: class switch recombination and somatic hypermutation Sµ µ δ Sγ3 γ3 Sε ε Sµ µ δ Sγ3 γ3 S Sε ε Sµ µ δ Sγ3 γ3 S Sε ε γ3 Sγ3 excision circle δ Sµ Sε ε µ SµSε Sε 1. (SR) diverse antibodies gg, ga, gg: longer half-life, binding to Fcγ receptors, complement activation ga: mucosae localization : anti-parasite infection 2. () efficient antibodies Mutations in regions selection of cells expressing a R with high affinity for antigen (role of follicular dendritic cells) 1

2 g class switch recombination deficiencies g class switch recombination deficiencies Serum g levels: Serum g levels: gg ga gg ga Defective T/ cooperation (50%) ntrinsic cell defect (50%) Defective T/ cooperation (50%) ntrinsic cell defect (50%) T/ cooperation deficiencies g SR-deficiencies caused by impaired T/ cooperation: -D40L or AR D40-deficiency D40L D40 TRMH L-R SR gg, ga, -linked D40L-deficiency (most frequent of g-sr deficiencies) AR-D40-deficiency (very rare cause of g-sr deficiency) Susceptibility to bacterial infections from the first years of e Lack of germinal centres in secondary lymphoid organs ontrol D40L -/- : T follicular helper, TR: T cell receptor, MH : major histocompatibility complex class, D40L: D40 Ligand, L-R: interleukine receptor, SR: g class switch recombination, : Defective SR and Associated T cell defect in D40L or D40-deficiency D40L/D40 deficiencies combine a and a T cell defect D40L T D4 (+) D40 TRAg HLA L-R Dendritic cell nterleukine production pro-inflammatory: L1, L6, TNFa, anti-infectious: L12,L18, mpaired cell immunity: susceptibility to bacterial infections (100%) mpaired T cell immunity susceptibility to opportunistic infections (100%) Liver disease: sclerosing cholangitis (20%) Neutropenia (68%) Auto-immunity (5%) ancers (3%) Susceptibility to viral and opportunistic infections Pneumocystis Jirovici, Giardia Lamblia, ryptosporidium 2

3 -D40L or AR D40-deficiency: dinosis and treatment D40-induced NF-k activation defect g levels (Normal or increased, decreased gg and ga) Neutropenia Decrease number of D27+ memory cells Defective expression of D40L on activated T cells (-linked D40L def.) or of D40 on cells (AR D40 def.) ontrol ontrol D40L D40 TRMH NEMO NF-κ L-R SR gg, ga, D40L on activated TD4 cells D40 on cells Genetic analysis : mutations in D40L or D40 genes Treatment: g, A, bone-marrow transplantation NF-κ: nuclear factor κ, NEMO: NF-κ essential modulator, SR: g class switch recombination, : g SR-deficiency associated to anhydrotic ectodermal dysplasia -linked anhydrotic ectodermal dysplasia g class switch recombination deficiencies Serum g levels: ariable defect in SR and Defective response to polysaccharidic antigens Hypomorphic mutations in NEMO (NF-k essential modulator) gg ga Treatment: g, A, bone-marrow transplantation Defective T/ cooperation (50%) ntrinsic cell defect (50%) g SR-deficiencies caused by an intrinsic cell defect D40L D40 S µ δ S γ3 S ε S µ δ S γ3 S S ε TRMH L-R AD, UNG,.. SR gg, ga, S µ δ S γ3 S S ε Error prone S S ε AD: Activation-nduced cytidine Deaminase, UNG: Uracil-N glycosylase SR: g class switch recombination, : 3

4 Sγ3 δ µ γ3 excision circle SµSε Sµ µ δ Sγ3 γ3 Sε ε Sµ µ δ Sγ3 γ3 S Sε ε Sµ µ δ Sγ3 γ3 S Sε ε Sµ Sε ε Sε g SR-deficiency caused by defective in and S regions Error prone S µ δ S γ3 S ε S µ δ S γ3 S S ε AD UNG S µ δ S γ3 S S ε S S ε AD: Activation-nduced cytidine Deaminase, UNG: Uracil-N glycosylase Activation-nduced cytidine Deaminase deficiency g SR-deficiencies caused by defective Autosomal recessive inheritance (consanguinity: 10-62%) Susceptibility to bacterial infections: 100% Lymphadenopathies: 50-72% g levels (Normal or increased, complete lack of gg and ga) Lymphadenopathies Normal number of D27+ memory cells ontrol Genetic analysis: Activation induced cytidine deaminase (AD) 40% Uracil-N glycosylase(1%) Most are molecularly undefined: AD cofactor?(60%) Auto-immunity: 21% (AHA, TP, A hepatitis, RA, LED ) Defective SR and Treatment: g substitution g SR deficiencies caused by defective of S regions S µ δ S γ3 S ε AD UNG S µ δ S γ3 S S ε An g SR-deficiency associated to a defect Autosomal recessive inheritance Susceptibility to bacterial infections (100%) Lymphadenopathies (50%) Error prone S µ δ S γ3 S S ε S S ε Mab anti-ad labelling control patient Autoimmunity (AHA, TP, SLE, uveitis) (21%) E(-) lymphoproliferative disorder (11%), AML (4%) Defective SR, normal 4

5 g SR-deficiency associated to a defect: dinosis and treatment g SR-deficiencies g levels (Normal or increased, decreased gg and ga) Decrease number of D27+ cells Molecularly undefined cell defect AR-UNG? T and cell defect Differential dinosis: Ataxia Telangiectasia++ Treatment: g substitution, follow-up++ AD cofactor? -L D40L opportunistic infections auto-immunity AR-AD -L NEMO AR-D40 AD NSERM U768 Paris, France A. Fischer M. Forveille P. Gardès S. Kracker A. Léger F. Mazerolles Acknowledgements All the clinicians, patients and their families ευχαριστώ UNG 5