A Boy with Severe Fatal Infections 11 Years of a Diagnostic Puzzle

A boy with severe fatal infections 11 years of a diagnostic puzzle J. Reichenbach University Children‘s Hospital Zurich Department of Immunology/Hematology/BMT The first contact • • • • • 15 mo: recurrent infections and lymphadenitis Length/weight 3rd percentile Complete routine vaccination, no BCG Non-consanguineous polish parents Empty family history Immunological work-up? Immunologists at work Low IgG and IgA, elevated IgM: HIGM? Normal CD40/CD40L expression AR-HIGM excluded (AID, UNG) Normal Lymphocyte subsets Normal mitogen proliferative response Impaired IFN- γ production (IL-2 ± anti-CD3) Dennis and his microbes • • 2 y, 4 y: M. avium adenitis 7 y: HiB and S. pneumoniae respiratory infections bronchiectasis • 9 y: disseminated M. avium osteomyelitis, dermatitis • 11 y: Extra-intestinal S. enteritidis • 12 y: fatal HSV1 encephalitis Treatment… and Diagnosis? • IVIG 400 mg/kg • 4-drug anti-mycobacterial regimen • S. c. IFN-γ • Repeated i. v. antibiotics Recurrent severe mycobacterial infection + low IFN- γ production: MSMD? MSMD? Ask Colleagues in Paris Humoral HIGM: Low IgG and IgA, high IgM No specific Ab to Tetanus and Diphteria Low specific Ab to HiB and PNC Cellular Normal numbers of T, B, NK cells Normal T but impaired B cell proliferation Absent IgD+CD27+ memory B cells IL-12/IFN- γ axis, TIR and TNF- α A C B D MSMD+ without mutation in known genes Molecular mechanism of bacterial disease? TIR family IL1 TLR AgR family TCR TNFR family TNF CD40 IKK-1 IKK-2 Mycobacteria Pneumococci NEMO NF-κB IκBα p50 p65 IFNγ IL12 TNFα Specific Ig NF-κB pathway Still more puzzling… EDA with immunodeficiency (EDA-ID) A “classical” PID: Pneumococcus Staphylococcus Haemophilus iB Mycobacteria CMV Pneumocystis … It’s NEMO! Stimuli NEMO α β IKK γ p I-κB p Cytoplasm NLS NF-κB Nucleus NEMO = NF-κB Essential Modulator = IKKγ NEMO stop codon mutations XD-IP, XR-EDA-ID, XR-ID without EDA Why alive at 11 y? N-terminally truncated NEMO Re-initiation of Translation at M38 0.63 0.51 0.27 (Kozakian AUG) B C WT NEMO encodes 2 proteins Think of NEMO … even in the absence of EDA TIR family IL1 TLR AgR family TCR TNFR family TNF CD40 IKK-1 IKK-2 Mycobacteria Pneumococci NEMO NF-κB IκBα p50 p65 IFNγ IL12 TNFα Specific Ig FSER Laboratory of Human Genetics of Infectious Diseases Streptococcus pneumoniae Horst von Bernuth Cheng-Lung Ku Estelle Chang Anne Puel Capucine Picard Mycobacterium Claire Fieschi Orchidée Dos Santos Jacqueline Feinberg L. de Beaucoudrey Ariane Chapgier Guillaume Vogt Claire Soudais Herpes simplex virus Céline Eidenschenk Shenying Zhang Manu Jouanguy Kun Yang Armanda Casrouge Laurent Abel Jean-Laurent Casanova