Primary Immunodeficiency PDF

Primary Immunodeficiency With Professor Peter J. Delves Learning Objectives Define primary immunodeficiency. Give examples of primary immunodeficiency diseases. Predict the types of opportunistic infections likely to be associated with particularly immunodeficiency states. Outline the...

Primary Immunodeficiency With Professor Peter J. Delves Learning Objectives Define primary immunodeficiency. Give examples of primary immunodeficiency diseases. Predict the types of opportunistic infections likely to be associated with particularly immunodeficiency states. Outline the therapeutic options available for the treatment of primary immunodeficiencies. Primary Immunodeficiency Defective immunity due to an inherited or acquired gene defect. Distribution of Cellular Primary Immunodeficiency Defects Type Primary immunodeficiency cases B-cell/antibody 50 % Combined T-cell and B-cell 20 % Phagocytes 20 % T-cell 10 % Primary Immunodeficiency Consequences Opportunistic infections Type of infections reflects the defect. Immunodeficiency affecting T-cells predominantly intracellular infections, e.g. viruses, mycobacteria Immunodeficiency affecting phagocytic cells, B-cells, complement mainly extracellular bacteria Primary Immunodeficiency Background Most primary immunodeficiencies are caused by an inherited gene defect, although some are due to spontaneous mutations. Inheritance may be autosomal recessive (both gene copies need to be defective) or autosomal dominant (only one copy needs to be defective). Primary Immunodeficiency Background Others are X-linked and therefore more common in males. Severity will vary depending on the nature of the mutation. Primary Immunodeficiency Background Manifest themselves in infancy Most primary immunodeficiencies have a low prevalence. Primary Immunodeficiency Background The study of primary immunodeficiencies has provided valuable insights into individual components of the human immune system. X-linked Primary Immunodeficiencies Gene PID PIG-A Paroxysmal nocturnal hemoglobinuria X Chromosome gp91phox Chronic granulomatous disease WASP Wiskott Aldrich syndrome Foxp3 Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) gc X-linked severe combined immunodeficiency (XSCID) MAGT1 NKG2D deficiency Btk X-linked agammaglobulinemia (XLA) SH2D1A X-linked lymphoproliferative disease type 1 (XLP1) XIAP X-linked lymphoproliferative disease type 2 (XLP2) CD40L X-linked hyper-IgM syndrome NEMO X-linked hyper-IgM syndrome Examples of Primary Immunodeficiency Affecting the Innate Response Complement deficiencies Paroxysmal nocturnal hemoglobinuria (PNH) Hereditory angioedema Chronic granulomatous disease (CGD) Myeloperoxidase deficiency Glucose-6-phosphate dehydrogenase deficiency Leukocyte adhesion deficiency Chediak-Higashi syndrome Autoinflammatory disorders Complement Deficiencies Defective gene Disorder Typical infections Impaired clearance of C1q, C1r, C1s, C2, C3, C4, immune complexes, Pyogenic bacteria Factor I systemic lupus erythematosus Disseminated Neisseria C5, C6, C7, C8, C9, Factor D, Deficiencies of these gonorrhoeae and N. Properdin components meningitidis MASP-2 MASP-2 deficiency Streptoccocus pneumoniae MBL deficiency MBL Usually none (prevalence ~ 5 %) Complement Regulatory Component Deficiencies GPI CD55 inhibits Paroxysmal nocturnal hemoglobinuria (PNH) C3 convertase Mutation in the PIG-A gene, encoding α-1,6-N- CD59 acetyl-glucosaminyltransferase, results in an prevents GPI inability to synthesize the glycosyl insertion of MAC phosphatidylinositol (GPI) anchors MAC Lack of GPI-anchored complement control proteins CD55 and CD59 on erythrocytes Erythrocytes susceptible to complement- mediated lysis Absence of CD55 and CD59 Complement Regulatory Component Deficiencies Hereditary angioedema C1 inhibitor (C1 esterase inhibitor) deficiency Coagulation system Complement system Kinin system Factor XIIa C1 Kallikrein C1 inhibitor C1 inhibitor C1 inhibitor Fibrin C3a, C5a, MAC Bradykinin Clotting Inflammation and cell lysis Endothelial cell activation Defects of Phagocytic Cells Defective gene Disorder Typical infections p22phox, p47phox, Chronic granulomatous disease Staphylococcus aureus, Aspergillus p67phox, p40phox, (CGD) fumigatus, Candida albicans or gp91phox CD18 b subunit Leukocyte adhesion deficiency I Pyogenic bacteria GDP-fucose Leukocyte adhesion deficiency II Pyogenic bacteria transporter Kindlin 3 Leukocyte adhesion deficiency III Pyogenic bacteria Staphylococcus aureus, Streptococcus pyogenes, LYST Chediak-Higashi syndrome Pneumococci, Aspergillus spp., Pseudomonas aeruginosa Chronic Granulomatous Disease O2.O - Defect in subunits of the 2 Phagocytic nicotinamide adenine vacuole dinucleotide phosphate (NADPH) oxidase Membrane p22phox Monocytes, gp91phox macrophages and NADP+ p47phox p40phox Cytosol neutrophils fail to H+ produce reactive oxygen intermediates p67phox NADPH Chronic Granulomatous Disease X-linked O2.O - gp91phox 2 Phagocytic vacuole Autosomal recessive p22phox Membrane p22phox gp91phox NADP+ p47phox p40phox Cytosol p47phox H+ p40phox p67phox NADPH p67phox Chronic Granulomatous Disease Myeloperoxidase or glucose-6-phosphate dehydrogenase mutations similar, less severe, phenotype Leukocyte Adhesion Deficiency Leukocyte adhesion deficiency (LAD) type I: lack of CD18 β subunit of the β2 integrins LAD type II: defective GDP-fucose transporter with inability to fucosylate sialyl Lewisx structures LAD type III: mutation of the integrin-activation molecule kindlin 3 b chain required to produce integrin heterodimer LAD I Correct glycosylation required for cell adhesion LAD II Conformational change required for integrin activation LAD III Chediak-Higashi Syndrome Defects in LYST (lysosomal trafficking) gene Accumulation of giant intracytoplasmic granules, due to defective migration of the late endosomal/lysosomal compartment within the cell, interferes with correct function of cells Dysfunction of neutrophils, NK-cells and cytotoxic T-cells Chediak-Higashi Syndrome Patients suffer from pyogenic infections, particularly with Staphylococcus aureus, Streptococcus pyogenes, Pneumococci, Aspergillus spp., Pseudomonas aeruginosa. Neutrophil NK Tc Autoinflammatory Disorders More than 30 autoinflammatory disorders, some monogenic, others polygenic Episodes of apparently unprovoked inflammation, fever, rashes, joint/muscle aches, abdominal/chest pain Dysregulated expression or control of pro-inflammatory cytokines Familial Mediterranean fever: pyrin mutations; an inflammasome regulator expressed in neutrophils and monocytes; Inflammasomes generate active caspase-1 which converts pro-IL-1b into active IL-1b Autoinflammatory Disorders Cryopyrin-associated periodic syndrome (CAPS): NLRP3 mutations; an inflammasome component Deficiency of the interleukin-1 receptor antagonist (DIRA): IL-1 receptor antagonist (IL-1RA) mutations; result in uncontrolled IL-1b activity TNF receptor-associated periodic syndrome (TRAPS): p55 TNF receptor mutations Hyper-IgD syndrome (HIDS, also called hyperimmunoglobulinemia D with periodic fever syndrome): mevalonate kinase mutations; indirectly lead to increased production of IL-1b Mutations Affecting T-cell Maturation CD4+ MHC Class II T-cell LCK CLP Pro-T Pre-T DP T cell UNC 119 γC RAG1 CORONIN 1A IL-7Rα RAG2 ORAI IL-2Rα ARTEMIS STIM-1 ZAP70 JAK3 CERNUNNOS TCRα TAP1,2 ADA DNA MST1 TAPASIN CD8+ PNP Ligase 4 RHOH T-cell DNAPKcs CD45 CD3 Mutations Affecting B-cell Maturation CLP Pro-B Pre-B ADA RAG1, RAG2 PNP ARTEMIS CERNUNNOS DNA ligase 4 DNAPKcs BTK, PI3K p85α, λ5 Igα Igµ chain BLNK LRRC8 Examples of Primary Immunodeficiency Affecting B-cells Common variable immunodeficiency X-linked agammaglobulinemia Selective IgA deficiency Common Variable Immunodeficiency Low IgG and IgA and/or IgM Gene defects in most patients have yet to be fully defined Common Variable Immunodeficiency Some CVID patients have mutations in: TAC1 CD19 ICOS Substance P MHC class II Complement components Mismatch repair protein MSH5 B-cell surface BAFF receptor S. pneumoniae, H. influenzae, Mycoplasma spp. infections X-Linked Agammaglobulinemia Mutations in tyrosine kinase (Btk) gene Developmental defect at pre-B-cell stage Btk Antibody production grossly compromised Pro-B Pre-B Recurrent infection with the pyogenic bacteria (Staphylococcus aureus, Streptococcus pyogenes and S. pneumoniae, Neisseria meningitidis, Haemophilus influenzae) and with the fungus Pneumocystis jirovecii Selective IgA Deficiency Both circulating IgA and secretory dimeric IgA are affected. Circulating IgA Gene defects in most patients unknown Majority of patients asymptomatic Mucosal Other classes of antibody (including IgM IgA transported to mucosal surfaces by poly-Ig receptor) compensate Examples of Immunodeficiencies Affecting T-Cells Defective gene Disorder Typical infections CD40L, CD40, AID, Pneumocystis jirovecii, Toxoplasma, Hyper-IgM syndrome NEMO or UNG Cryptosporidium parvum Extracellular bacteria, staphylococci, STAT3, TYK2, DOCK8 Hyper-IgE syndrome Aspergillus spp., Candida albicans TBX1 DiGeorge syndrome Multiple WASP Wiskott Aldrich syndrome Encapsulated extracellular bacteria TAP1, TAP2 or tapasin MHC class I deficiency Bronchopulmonary CIITA MHC class II deficiency Bronchopulmonary Hyper-IgM Syndrome Raised serum IgM and IgD Very low or absent IgG, IgA and IgE NEMO AID Most patients have X-linked form: CD40L or less commonly NEMO (NFκB essential modifier, UNG alternatively known as IKKg) Autosomal CD40, activation-induced cytidine deaminase (AID) or uracil-DNA glycosylase (UNG) Th B CD40L CD40 Recurrent bacterial infections Hyper-IgE Syndrome Cytokine receptor Immune dysregulation IgE eosinophils, B- cells, NK-cells CD8+ T-cell proliferation and JAK TYK2 activation P P P P Autosomal dominant mutation in STAT3 or STAT3 STAT3 autosomal recessive mutations in TYK2 or DOCK8 STAT3 STAT STAT3 and TYK2: P P dimerization Signaling through several cytokine receptors STAT3 Gene transcription Hyper-IgE Syndrome MyD88 Endosomal PRR DOCK8: Actin cytoskeleton Actin DOCK8 cytoskeleton rearrangement PYK2 PAMP DiGeorge Syndrome Mutations in TBX1 transcription factor involved in embryonic development Failure of the thymus to develop Cell-mediated immune responses are Th Treg Tc undetectable. DiGeorge Syndrome Antibody responses poor due to lack of T-cell help Complete absence of thymus relatively rare, more commonly partial DiGeorge syndrome with some T-cells Th Treg Tc Treatment by grafting neonatal thymus Wiskott-Aldrich Syndrome Defective Wiskott Aldrich syndrome protein (WASp) Compromised T-cell motility, phagocyte chemotaxis, dendritic cell trafficking and the polarization of T-cell cytoskeleton towards B-cells during T B collaboration Wiskott-Aldrich Syndrome In the early phases of T-cell activation, the adhesion molecules are scattered randomly across the surface. Activation of WASP by ZAP-70 induces the actin cytoskeleton to form an immunological synapse. Nairn, Roderick: Immunology for Medical Students. 2nd Edition. Elsevier. 2007. Fig 31.9 MHC Class I Deficiency Mutations in TAP1, TAP2 or Tapasin MHC I pMHC class I TAP1 presented to TAP2 CD8+ T-cell ER Immunoproteasome Tapasin Peptides Calreticulin Protein (8 9 amino acids long) Ubiquitination Erp57 MHC Class II Deficiency Thymic cortex Positive selection CD4+: Thymic medulla Secondary rescue from apoptosis Negative selection lymphoid tissues CD4-CD8- CD4+CD8+ CD4+ Thymic T-cell T-cell epithelial cell T-cell MHC Class II Deficiency Class II transactivator (CIITA) mutations affecting transcription factors controlling class II gene expression Low expression of class II molecules on thymic epithelium impairs positive selection of CD4+ T-cells Recurrent bronchopulmonary infections and chronic diarrhea occurring within the first year of life Death from overwhelming viral infections at ~4 years unless given hematopoietic stem cell transplant Primary Immunodeficiencies Associated with Autoimmune Disease Foxp3 mutations: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome Unregulated T-cell activity leading to multisystemic and often fatal autoimmune disease Primary Immunodeficiencies Associated with Autoimmune Disease AIRE mutations: autoimmune polyendocrine syndrome-1 (APS-1, or APECED autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy) Defective central tolerance of T-cells Primary Immunodeficiencies Associated with Autoimmune Disease Fas (CD95) or fas ligand (CD95L) mutations: autoimmune lymphoproliferative syndrome (ALPS) Defective lymphocyte apoptosis Severe Combined Immunodeficiency (SCID) Mutations in one of a number of genes controlling cytokine signaling, TCR signaling, VDJ recombination or metabolism Complete failure of T-cell development Affects approximately one child in every 80,000 live births Severe Combined Immunodeficiency (SCID) Severe defects in both cellular and humoral immunity Severe and recurrent viral, bacterial and fungal opportunistic infections Without treatment fatal within first year of life Severe Combined Immunodeficiency (SCID) Phenotype Genetic defect T-B+NK- gC, JAK3 RAG-1, RAG-2, Artemis, DNA ligase IV, Cernunnos, T-B-NK+ DNA PKcs IL-7Rα, CD3d, CD3e, CD3z, Coronin-1A, ZAP-70, T-B+NK+ CD45 T-B-NK- Adenosine deaminase (ADA), AK2 Severe Combined Immunodeficiency (SCID) T-B+NK- gC (X-linked) or JAK3 (autosomal recessive) mutations account for approx 50% of SCID cases. IL-2R IL-4R IL-7R gC gC gC JAK1 JAK3 JAK1 JAK3 JAK1 JAK3 Severe Combined Immunodeficiency (SCID) T-B+NK- gC (X-linked) or JAK3 (autosomal recessive) mutations account for approx 50% of SCID cases. IL-9R IL-15R IL-21R gC gC gC JAK1 JAK3 JAK1 JAK3 JAK1 JAK3 Diagnosis of Primary Immunodeficiency Tests T-lymphocytes B-lymphocytes Phagocytes Complement Enumeration CD3+ lymphocytes CD20+ lymphocytes Neutrophil count CD4+, CD8+ subsets lg+ cells immunoglobin levels Assessment of in PHA stimulation NBT test (nitroblue Hemolysis assay vitro functioning antigen-specific tetrazolium) stimulation IL-2 production Assessment of in Delayed Specific antibody vivo functioning hypersensitivity levels: reaction to purified isohemagglutinins; protein derivative anti- E-coli; anti- (PPD) of M. tetanus, anti- tuberculosis diphtheria toxins (with booster injections if necessary) Treatment of Primary Immunodeficiency Early intervention with antibiotics and antifungals Long-term low-dose prophylactic antimicrobials to prevent reinfection Cytokine therapy with G-CSF to boost neutrophil numbers in patients with neutropenia IFNg to stimulate phagocytes in patients with CGD Treatment of Primary Immunodeficiency IL-2 to stimulate lymphocytes in patients with CVID Intravenous or subcutaneous pooled human immunoglobulin (to replace missing antibodies in B-Cell immunodeficiencies) Intramuscular bovine ADA conjugated to polyethylene glycol Bone marrow, cord blood or adult peripheral blood hematopoietic stem cell transplantation (to replace missing immune cells) Gene therapy Gene Therapy of Primary Immunodeficiency + hematopoietic stem cells SCID: ADA or gc Wiskott-Aldrich syndrome: Wiskott-Aldrich syndrome protein (WASp) Chronic granulomatous disease: gp91phox Learning Outcomes ✓ How to define primary immunodeficiency. ✓ Examples of primary immunodeficiency diseases. ✓ To predict the types of opportunistic infections likely to be associated with particularly immunodeficiency states. ✓ Therapeutic options available for the treatment of primary immunodeficiencies. List of References Basic and Clinical Immunology for Medical Immunology, 2nd Edition Students, 2nd Edition Peakman Nairn