Transcript deficiency
Immunodeficiencies Anna Šedivá Institute of Immunology, University Hospital Motol Evolution of immunity Billions of years 4.5 3.5 procaryota, bacteria 1.5 eucaryota 0.5 organisms Evolution of immunity procaryota invertebrates vertebrates lymphatic organs HLA Evolution of immunity An ancient evolutionary origin of genes associated with human genetic diseases Tomislav Domazet-Lo and Diethard Tautz Max-Planck Institut für Evolutionsbiologie Accepted for publication September 19, 2008 Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be nonessential genes (i.e. are not embryonically lethal when inactivated) and one could therefore speculate that they are late additions in the evolutionary lineage towards humans. Contrary to this expectation, we find that they are in fact significantly over-represented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome, but are biased towards ancient genes. Immne system and its function useful x damaging defense of organisms immune surveillance tolerance repeated infections immunodeficiencies pathological reaction to environmental antigens pathological reaction to internal antigens allergy defects in immune surveillance oncological diseases autoimmunity Common defense mechanisms • skin and mucosa • cilia, mucus • hydrochloric acid • urine • tears Innate and aquired immunity • • • • • • innate immunity humoral complement cellular phagocytes, NK cells aquired immunity humoral antibodies cellular T lymphocytes defense against bacteria, some viruses bacteria, fungi defense against extracelul. bact., neutralization of viruses intracel. bact., fungi, viruses Immunodeficiencies 1. primary innate diseases genes coding for immune system components 2. secondary secondary immune disorders based on primary cause Primary immunodeficiencies humoral ( 70%) cellular and combined ( 20%) phagocytosis ( 10%) complement ( 1%) incidence 1:500-700 (IgAdef.) 1:100 000 (SCID) Development of immune system • development of cellular immunity - hematopoiesis • antibodies IgM • FcRn • cytokines IgG IgA birth 6 months Vaccination 1796 Edward Jenner (1749-1823) variolla 1885 Louis Pasteur (1822-1895) rabies Vaccination calendar DIFERENTIAL DIAGNOSIS OF PRIMARY IMMUNODEFICIENCIES humoral cellular and phagocytosis complement combined frequency 70% clinical after 6.months problems - adulthood. 20% 10% 1% birth - 2 years birth - 2 years individual child, adult. autoim. SLE pyogenic inf. oedema clinical picture respiratory inf. pneumonias otitides arthritides respir.inf. pneumonias diarhoea dermatitides omfalitis adenitides pyodermias otitides cause extracel. microorg. echoviruses viruses fungi mycobakteria stafylococci Neisseria fungi enterobacteria DIFERENTIAL DIAGNOSIS OF PRIMARY IMMUNODEFICIENCIES humoral cellular and combined phagocytosis complement vaccination enteroviral vaccines live vaccines BCG vaccine individual survival adulthood early childhood individual individual complications cardiovascul. problems echoviral infections m.BrutonXLA CVID IgA def. infection tumors autoimmunity infections various SCID chronic hereditary granulomatosis angioedema, LAD syndrom deficiencies of indiv.components clinical diseases Humoral immunodeficiencies diseases: T lymphocyte Bruton agammaglobulinemia IgA deficiency IgG subclass deficiency CVID (common variable immunodeficiency) hyper IgM syndrom Wiskott Aldrich syndrom CD40L CD40 B lymphocyte Humoral immunodeficiencies Bruton agammaglobulinemia X linked agammaglobulinemia 1952 Dr.Bruton 1993 gene, btk, Xq21.3-22 pre B lymphocyte B lymphocyte Humoral immunodeficiencies Hyper IgM syndrom X linked gen, Xq26 CD40L T lymphocytes T lymphocyte CD40L CD40 autosomal recessive susp. gen 12p13 AID (activation induced cytidinedeaminase) somatic hypermutation deficiency B lymphocyte Humoral deficiencies Lack of B lymfocytes, decrease of all Ig: X-linked agammaglobulinemia, μ-Heavy chain deficiency, Igα deficiency, BLNK deficiency, thymoma with immunodeficiency Low B ly, low at least 2 Ig isotypes: common variable immunodeficiency (CVID), ICOS deficiency, CD19 deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency Normal B, low IgG,IgA, normal or high IgM: CD40L def.,AID deficiency, UNG deficiency, CD40 def.,NEMO Normal B, low isotpyes or light chains: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subsclass deficiency, selective immunoglobulin A deficiency Deficit of specific Ab: transient hypogammaglobulinemia of infancy ID, B lymphocytes BCR HLA I. TAP1,2 BLNK BTK CIITA HLA II. SLAM Cellular and combined immunodeficiencies diseases: SCID di George syndrome reticular dysgenesis ADA deficiency gamma chain of interleukin receptor deficiency PNP deficiency deficiency MHC II. třídy deficiency ZAP-70 Omenn syndrome Cellular defects SCID ID, T lymphocytes TCR e CD3 CD4 g z cytokine receptor ZAP-70 p56lck CD154 CD40L SLAM g JAK-3 WASP NFAT Screening - SCID Možnost Tx kmenových hematopoetických buněk Tx do 3,5 měsíce věku 94% úspěšnost, poté klesá na 70% (R.Buckley) Česká republika 1:100 000 1-2 případy ročně Tx pro PID od 1994 SCID 13 dětí mortalita 80% Screening Human B- andT-cell differentiation stages including V(D)J recombination bars (Dik et al., 2005; van Zelm et al., 2005) and genetic defects underlying PID that result in impaired precursor differentiation. Screening -TRECs T cell Receptor Excision Circles (TRECs). TRECs are episomal DNA circles produced in thymocytes by excisional rearrangements of T cell receptor (TCR) genes; they are stable, not duplicated during mitosis, diluted out with each cell division, and therefore higher in thymocytes, recent thymic emigrants (RTEs) and naïve T cells. Quantitative polymerase chain reaction (PCR) of coding-joint (cj) δRec ψJα TREC, produced at TCRα/δ locus within chromosome 14 (14q11) by > 70% of developing human α:β T cells, counts in the peripheral blood naïve α:β T lymphocytes recently dismetted by thymus: in newborn, values < 25 TRECs/μL indicate SCID. Cossu Italian Journal of Pediatrics 2010 36:76 doi:10.1186/1824-7288-36-76 Screening - TRECs a KRECs Newborn screening CATCH 22 Several clinical conditions caused by the mutations located in the same region form the cluster of diseases called CATCH 22. cardiac defects, abnormal facies, thymic hypo/aplasia, cleft palate, hypocalcemia, deletion 22q11 Chromosome 22q11 deletion syndrome is probably better employed in the description of this condition. The poster for film remake of famous novel of Joseph Heller CATCH-22. Well known symbolic name was used as a sample for CATCH-22 syndrome. Cellular and combined deficiencies T-/B+ SCID γc deficiency, JAK3 deficiency, interleukin 7 receptor chain α deficiency, CD45 deficiency, CD3δ/CD3ε deficiency. T-/B- SCID RAG 1/2 deficiency, Omenn syndrome adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency DNA ligase type IV deficiency, Artemis deficiency CD40 ligand deficiency, CD40 deficiency MHC class II deficiency CD3γ deficiency, CD8 deficiency, ZAP-70 deficiency TAP-1/2 deficiency Reticular dysgenesis Deficiency of phagocytosis diseases: chronic granulomatosis LAD syndrom 1, 2 deficiency of myeloperoxidase deficiency of G6PD Chédiak-Higashi syndrome neutropenia LAD syndrom adhesion molecules LAD syndrome I. CD 18 Phagocytic immunodeficiencies Chronic granulomatosis inability of phagocyts to generete reactive oxygen radicals gene defect of one or more components of NADPH oxidase X - linked defect in genefor gp91-phox membrane bound part of the molecule of cytochrom b558 autosomal recesive defect in genes of membrane or cytoplasmatic subunits p47-phox, p67-phox, p22-phox NADPH oxidase membrane and cytoplasmatic subunits phagocyte Phagocytic deficiencies Neutropenias Severe congenital neutropenia: ELA2 deficiency (with myelodysplasia), G-CSFR deficiency Kostmann syndrome, Cyclic neutropenia, X-linked neutropenia/myelodysplasia, Shwachman-Diamond syndrome LAD Leukocyte adhesion deficiency types 1, 2 and 3 Functional defects Chronic granulomatous disease: X-linked, AR Neutrophil glucose-6-phosphate dehydrogenase deficiency Specific granule deficiency Susceptibility to mycobacteria IL-12 and IL-23 β1 chain deficiency,IL-12p40 deficiency Interferon γ receptor deficiency, STAT1 deficiency Complement deficiencies diseases: deficiencies of early components of complement cascade deficiencies of late components of complement cascade angioneurotic oedema deficiencies in alternative complement pathway Innate immune deficiencies TLR membrane TLR intracelular Intracelular sensors -NLRs, Nod1, Nod2, Ipaf and NALPs -RIG-I a Mda-5 Innate immunity herpetic encefalitis – TLR3, UNC-93B pneumococcal infections – IRAK4 Anhydrotic epidermal dysplasia, viral infections - NEMO interferon production defects Mycobacterial susceptibility IL 12 (IL 23) – IFN g Susceptibility to Mycobacteria Recessive, loss of function Recessive, non functional molecule Recessive, partial deficiency Dominant, partial deficiency Combined immunodeficiencies Hyper IgE syndrom Eczema, cold abscesses, Staf. Infections, skin and lungs, candidiasis, face features, dental problems, joints and skeletal problems High IgE, eosinofilia HIES scoring system (NIH) (1999) 19 (>40 suspected HIES, <20 unlikely dg) HIES – scoring system, 2010 • • • • • • • • • recurrent pneumonia eczema recurrent skin abscesses characteristic face failure to shed deciduous teeth lung cyst formation eosinophilia newborn rash other unusual infections • • • • • • • • • increased interalar distance cathedral palate hyperextensibility pathologic bone fractures recurrent upper respiratory infections candidiasis scoliosis midline anomaly IgE, Th17 0-8 HIES >30 STAT3 mutace 5 typických znaků Woellner et al: Mutations in STAT3 and diagnostic guidlines for HIES, J Allergy Clin Immunol, february 2010 HIES – AD 2007 – mutace v „signal transducer and activator of transcription 3 (STAT 3) Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature, Aug 2007 Holland SM, Deleo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM, Grimbacher B. STAT3 Mutations in the Hyper-IgE Syndrome. NEJM Sep 2007 HIES HIES Prenatal diagnostics history, affected sibling ID with known gene, possible molecular diagnostics XLA some forms of SCID WAS AT chronic granulomatosis All known genes Prenatal diagnostics history, affected sibling ID with known phenotype, possible functional diagnosis from fetal blood XLA SCID syndrome diGeorge LAD chronic granulomatosis Investigation of primary immunodeficiencies • history • clinical examination • laboratory investigation – – – – – – – – blood count immunoglobulins specific antibodies lymphocytes complement phagocytic cells genetics other Therapy of primary immunodeficiencies substitution with immunoglobulins intravenous immunoglobulins indication Bruton agammaglobulinemia CVID hyperIgM syndrome Wiskott-Aldrich syndrome phagocytic deficiencies others subcutaneous immunoglobulins Therapy of primary immunodeficiencies antibiotic and antimycotic therapy chronic granulomatosis LAD bone marrow transplantation SCID LAD Wiskott-Aldrich syndrome Interferon g chronic granulomatosis G-CSF a GM-CSF neutropenia gene therapy ADA deficiency X -linked SCID (LAD, chronic granulomatosis.) other forms of therapy Gene therapy deficit ADA X - SCID (LAD, CGD..) Gene therapy a | In patients with severe combined immune deficiency (SCID), blocked lymphocyte production leads to immune deficiency. Blood cells are produced by the proliferation and differentiation of pluripotent haematopoietic stem cells (HSCs) through stages of lineage-restricted progenitors, the common lymphoid progenitor (CLP) and the common myeloid progenitor (CMP).These yield mature blood cells, including B cells (B), T cells (T), natural-killer cells (NK), granulocytes (Gran), monocytes (Mono), platelets (Plat) and erythrocytes (RBCs). Inherited mutations of genes that are needed for the production, survival or function of lymphocytes can cause severe combined immune deficiency (SCID), with absent or non-functional B, T and NK cells. b | The block to immune-cell production that occurs in patients with SCID leads to expansion of the progenitor-cell pool (CLPs). The number of CD34+ haematopoietic stem and progenitor cells obtained from the bone marrow of the youngest infant with X-linked SCID was relatively high for their size. This finding indicates that the pool of progenitor cells could be expanded in patients with X-linked SCID because of the absence of the c-chain, which is required for cytokine signalling and differentiation of CLP. c | Gene correction of haematopoietic and progenitor cells leads to immune reconstitution. In gene therapy for X-linked SCID, a retroviral vector was used to transfer the normal human c cDNA into HSCs that were isolated from the patient's bone marrow. Expression of c restores the cytokine response and allows differentiation of CLP to B, T and NK cells, yielding immune reconstitution. The success in immune reconstitution in these patients might be due to the large pool of progenitor cells that were available for transduction, and to the high level of engraftment of the genetically altered cells, due to the absence of endogenous mature lymphocytes. Secondary imunodeficiencies HIV reverse transcription HIV RNA transcription DNA CD4 proteases Secondary immunodeficiencies central lymphatic organs bone marrow, thymus, spleen number and function of peripheral leucocytes secondary antibody deficiencies metabolic diseases, malnutrition, hypovitaminosis therapy, surgery, intensive care infection tumors Primary immunodeficiencies Oxford University Press 1999 90 diseases 2011 WHO/IUIS classification there are 181 PIDs Oxford University Press 2006 140 diseases Autoinflammatory disorders imunotherapy Research T and B cells in diGeorge syndrom Switched memory B cells 45 40 35 30 25 20 15 10 5 0 35 Samples 30 Controls Sample averages Control 5./95. percentile % of CD19+ cells % of CD19+ cells Transitional B cells 20 Controls 15 10 Sample averages 5 0 Age groups (3 months - 20 years) Samples 25 Age groups (3 months - 20 years) Control 5./95. percentile