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![ Immune System
- defense mechanisms to protect the host from microbes
and their virulence factors]
• 3 Key Properties:
1. highly diverse antigen receptors
2. immune memory
3. immunologic tolerance](https://image.slidesharecdn.com/rheumacopy-140811033459-phpapp02/85/Rheuma-copy-2-320.jpg)
Uploaded byCherrie Anne Sierra
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The document discusses primary immunodeficiencies (PIDs), which are genetic disorders caused by defects in the immune system. It describes several key properties of the immune system and outlines deficiencies that can occur in both the innate and adaptive immune systems. Specific PIDs are then discussed in detail, including symptoms, diagnosis, and treatment options. The document emphasizes the importance of early diagnosis and molecular testing to determine the suitable treatment for each PID.
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- 2. Immune System -defense mechanisms to protect the host from microbes and their virulence factors] • 3 Key Properties: 1. highly diverse antigen receptors 2. immune memory 3. immunologic tolerance
- 3. 1. Innate ImmuneSystem - rapid triggering of inflammatory responses - all cell lineages 2. Adaptive Immune System - mediated by T and B lymphocytes - antigen-presenting cells
- 4. - expression orfunction of gene products is genetically impaired - Mendelian inheritance - overall prevalence of PIDs ~ 5 per 100,000 individuals - combination of recurrent infections, inflammation and autoimmunity
- 5. - presence ofrecurrent or unusually severe infections - detailed personal and family medical history genetic tests – Definitive Diagnosis
- 11. Deficiency of theInnate System 1. Severe Congenital Neutropenia impaired neutrophil counts (<500 /L of blood) absence of pus premature cell death of granulocyte precursors Diaqnosis: - bone marrow (block in granulopoiesis at the promyelocytic stage
- 12. Treatment: - hygiene -trimethoprim/sulfamethoxazole - SQ injection (G-CSF
- 13. 2. Asplenia infectionsby encapsulated bacteria Diagnosis: - abdominal UTZ - Howell-Jolly bodies
- 14. Treatment: - oralpenicillin - vaccination
- 15. 3. Leukocyte AdhesionDeficiency (LAD) a. LAD I - Most common - caused by mutations in the 2 integrin gene
- 16. b. LAD II -extremely rare - defect in selectin-mediated leukocyte c. LAD III - defect in a regulatory protein - can develop bleeding - causes impaired wound healing and delayed loss of the umbilical cord
- 17. • pus-free skin/tissueinfections and massive hyperleukocytosis (>30,000/L) • Diagnosis: - Immunofluorescence Treatment: - Hematopoietic Stem Cell Transplantation (HSCT)
- 18. 4. Chronic GranulomatousDiseases - impaired phagocytic killing of microorganisms by neutrophils and macrophages - incidence is approximately 1 per 200,000 live births - causes deep-tissue bacterial and fungal abscesses in macrophage-rich organs
- 19. Infectious Agents: -Staphylococcus aureusand Serratia marcescens -Burkholderia cepacia - Fungi (Aspergillus)
- 20. - defective productionof reactive oxygen species in the phagolysosome membrane - results from the lack of a component of NADPH oxidase Treatment: - trimethoprim/sulfamethoxazole - Daily administration of azole derivatives (intraconazole) - HSCT
- 21. 5. Mendelian Susceptibilityto Mycobacterial Disease - defect in the IL-12 interferon (IFN) leading to impaired IFN--dependent macrophage activation - Tuberculous & nontuberculous mycobacteria -- Hallmark - prone to developing Salmonella infections - Treatment: interferon
- 22. 6. Toll-Like Receptor(TLR) Pathway Deficiencies - specific susceptibility to herpes simplex encephalitis - Susceptibility to both invasive, pyogenic infections and mycobacteria
- 23. 7. Complement Deficiency -composed of plasma proteins that leads to the deposition of C3b fragments - deficiency in classic pathway (C1q, C1r, C1s, C4, and C2) can predispose an individual to bacterial
- 24. Diagnosis: - functionalassays (CH50 and AP50 tests) Treatment: - daily administration of oral penicillin
- 25. PRIMARY IMMUNODEFICIENCIES OFTHE ADAPTIVE IMMUNE SYSTEM (T Lymphocyte Deficiencies)
- 26. 1. SEVERE COMBINEDIMMUNODEFICIENCIES - complete absence of these cells (block in T cell development) - estimated to be 1 in 50,000 to 100,000 live births Clinical Manifestations: - recurrent oral candidiasis - failure to thrive - protracted diarrhea - acute interstitial pneumonitis caused by Pneumocystis jiroveci
- 27. Diagnosis: - Lymphocytopenia -- absence of a thymic shadow on a chest x-ray - determination of the number of circulating T, B, and NK lymphocytes– (Accurate Diagnosis)
- 28. • Mechanisms: a. Cytokine-SignalingDeficiency - most frequent SCID phenotype - absence of both T and NK cells
- 29. b. Purine MetabolismDeficiency - deficiency in adenosine deaminase (ADA) - induce premature cell death of lymphocyte progenitors - cause bone dysplasia with abnormal costochondral junctions and metaphyses and neurologic defects
- 30. c. Defective Rearrangementsof T and B Cell Receptors - selective deficiency in T and B lymphocytes - account for 20-30% of SCID - Can cause developmental defects
- 31. d. Defective (Pre-)TCell Receptor Signaling in the Thymus - deficiencies in CD3 subunits associated with the (pre)TCR and CD45 e. Reticular Dysgenesis - causes T and NK deficiencies with severe neutropenia and sensorineural deafness - results from an adenylate kinase 2 deficiency
- 32. f. Defective Egressof Lymphocytes - very low T cell counts - result from a deficiency in coronin-1A Treatment: - anti-infective therapies - immunoglobulin replacement - parenteral nutrition support - HSCT - a pegylated enzyme
- 33. THYMIC DEFECTS -profound T cell defect a. DiGeorge syndrome -constellation of developmental defects -thymus is completely absent Diagnosis - Immunofluorescence (hemizygous deletion in the long arm of chromosome 22)
- 34. b. CHARGE -coloboma ofthe eye, heart anomaly, choanal atresia, retardation, genital and ear anomalies syndrome Treatment: thymic graft
- 35. OMENN SYNDROME -erythrodermia, alopecia, hepatosplenomegaly and failure to thrive - T cell lymphocytosis, eosinophilia, and low B cell count Treatment: HSCT
- 36. FUNCTIONAL TCELL DEFECTS - partially preserved T cell differentiation - Causes chronic diarrhea and failure to thrive - Diagnosis: - Phenotyping - in vitro functional assays
- 37. a. Zeta-Associated Protein70 (ZAP70) Deficiency - complete absence of CD8+ T cells b. Calcium Signaling Defects - defective antigen receptor-mediated Ca2+ influx - prone to autoimmune manifestations (blood cytopenias) and nonprogressive muscle disease
- 38. c. Human Leukocyteantigen(HLA) Class II Deficiency - low but variable CD4+ T cell counts - defective antigen-specific T and B cell responses - susceptible to herpesvirus, adenovirus and enterovirus infections and chronic gut/liver Cryptosporidium infections
- 39. d. HLA ClassI Deficiency - reduced CD8+ T cell counts - loss of HLA class I antigen expression - cause chronic obstructive pulmonary disease and severe vasculitis
- 40. a. Ataxia-Telangiectasia (AT) -autosomal recessive disorder - causes B cell defects - progressive T cell immunodeficiency - hallmark features: telangiectasia and cerebellar ataxia - young children with IgA deficiency
- 41. Diagnosis: - cytogeneticanalysis (chromosomes 7 and 14) Treatment: immunoglobulin replacement
- 42. b. Nijmegen BreakageSyndrome (NBS) - severe T and B cell combined immune deficiency with autosomal recessive inheritance - exhibit microcephaly and a bird-like face - risk of malignancies is very high - deficiency in Nibrin caused by hypomorphic mutations
- 43. c. Dyskeratosis Congenita(Hoyeraal-Hreidarsson Syndrome) - absence of B and NK lymphocytes - progressive bone marrow failure, microcephaly, in utero growth retardation and gastrointestinal disease
- 44. d. Immunodeficiency withCentromeric and Facial Anomalies (ICF) - mild T cell immune deficiency with a more severe B cell immune deficiency - Features: coarse face, digestive disease, and mild mental retardation Diagnostic: - cytogenetic analysis
- 45. - elevated serumIgE levels Autosomal Recessive Hyper-IgE Syndrome - T and B lymphocyte counts are low - recurrent bacterial infections in the skin and respiratory tract - pox viruses and human papillomaviruses
- 46. - mutation inthe gene encoding the transcription factor STAT3 - combination of recurrent skin and lung infections complicated by pneumatoceles - caused by pyogenic bacteria and fungi Features: - facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis - Elevated serum IgE levels
- 47. - caused bymutations in the RMRP gene for a noncoding ribosome-associated RNA - short-limb dwarfism, metaphyseal dysostosis and sparse hair - can predispose to erythroblastopenia, autoimmunity, and tumors
- 49. - B cellimmune deficiency - leads to profound deficiency (IgG, IgA, and IgE) - prone to opportunistic infections (interstitial pneumonitis), cholangitis (Cryptosporidium) and infection of the brain (Toxoplasma gondii)
- 50. - incidence ofapproximately 1 in 200,000 live births - caused by mutations in the WASP gene - relative CD8+ T cell deficiency with low serum IgM levels and decreased antigen-specific antibody responses - clinical manifestations: recurrent bacterial infections, eczema, and bleeding
- 51. - Complications: bronchopulmonaryinfections, viral infections, severe eczema, autoimmune manifestations, lymphoma - Thrombocytopenia can be severe - typical feature: reduced-sized platelets on a blood smear
- 52. Diagnosis: intracellularimmunofluorescence analysis of WAS protein Treatment: - Prophylactic antibiotics, immunoglobulin G (IgG) supplementation, topical treatment of eczema - splenectomy improves platelet count - Allogeneic HSCT is curative
- 53. - account for60-70% of all cases - B lymphocytes antibodies: IgM, IgG, IgA Defective antibody production results to: - invasive, pyogenic bacterial infections - recurrent sinus and pulmonary infections (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis)
- 54. - Parasitic infections(Giardia lambliasis) bacterial infections (Helicobacter and Campylobacter) of the gut - infections rarely occur before the age of 6 months Diagnosis: - determination of serum Ig levels - Determination of antibody production - B cell phenotype determination in switched and nonswitched memory B cells
- 55. - complete lackof antibody production - mutation in the BTK gene - severe, chronic, disseminated enteroviral infections - Diagnosis: examination of bone marrow B cell precursors - Treatment: immunoglobulin replacement
- 56. - characterized bydefective Ig CSR - results in very low serum levels of IgG and IgA and elevated or normal serum IgM levels - have enlarged lymphoid organs - result from fetal rubella syndrome Diagnosis: - screening for an X-linked CD40L deficiency and an autosomal recessive CD40 deficiency
- 57. - characterized bylow serum levels of one or more Ig isotypes - prevalence is estimated to be 1 in 20,000 - develop lymphoproliferation (splenomegaly), granulomatous lesions, colitis, antibody-mediated autoimmune disease, and lymphomas
- 58. Diagnosis: - shouldexclude the presence of hypomorphic mutations associated with agammaglobulinemia or more subtle T cell defects
- 59. - IgA deficiency-- most common - increased numbers of acute and chronic respiratory infections (bronchiectasis) - increased susceptibility to drug allergies, atopic disorders, and autoimmune diseases - IgA deficiency may progress to CVID Treatment: immunoglobulin replacement
- 60. - prone toS. pneumoniae and H. influenzae infections of the respiratory tract - Defective production of antibodies against polysaccharide antigens - a defect in marginal zone B cells, a B cell subpopulation involved in T-independent antibody responses
- 61. -IgG antibodies havea half-life of 21-28 days Treatment: - injection of plasma-derived polyclonal IgG (repeated every 3-4 weeks, with a residual target level of 800 mg/mL in patients who had very low IgG level) - Immunoglobulin replacement can be performed by IV or subcutaneous routes (800 mg/mL once a week)--lifelong therapy main goal is to reduce the frequency of the respiratory tract infections and prevent chronic lung and sinus disease
- 62. a. Hemophagocytic Lymphohistiocytosis -unremitting activation of CD8+ T lymphocytes and macrophages that leads to organ damage (liver, bone marrow, and CNS) - results from impair T and NK lymphocyte cytotoxicity - EBV is the most frequent trigger
- 63. Clinical Features: -fever, hepatosplenomegay, edema, neurologic diseases, blood cytopenia, increased liver enzymes, hypofibrinogenemia, high triglyceride levels, elevated markers of T cell activation
- 64. Diagnosis: - Functionalassays of postactivation cytotoxic granule exocytosis The conditions can be classified into three subsets: 1. Familial HLH with autosomal recessive inheritance, including perforin deficiency
- 65. 2. HLH withpartial albinism - hair examination can help in the diagnosis - Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky Pudlak syndrome type II
- 66. 3. X-linked proliferativesyndrome (XLP) - induction of HLH following EBV infection - May develop progressive hypogammaglobulinemia - life-threatening complication Treatment: -immunosuppression (cytotoxic agent VP-16 or anti-T cell antibodies) - HSCT
- 67. - nonmalignant Tand B lymphoproliferation - caused by a defect in Fas-mediated apoptosis of lymphocytes - causing splenomegaly and enlarged lymph nodes - Hallmark: CD4 -CD8- TCR+ T cells (20-50%)
- 68. - 70% ofpatients also display autoimmune manifestations (autoimmune cytopenias, Guillain-Barre syndrome, uveitis, and hepatitis) Treatment: pro-apoptotic drugs
- 69. - Several PIDscan cause severe gut inflammation a. Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX) - caused by loss-of-function mutations in the gene encoding the transcription factor FOXP3 - widespread inflammatory enteropathy, food intolerance, skin rashes, autoimmune cytopenias and diabetes Treatment: allogeneic HSCT
- 70. b. Autoimmune PolyendocrinopathyCandidiasis Ectodermal Dysplasia (APECED) Syndrome - mutations in the autoimmune regulator (AIRE) gene - Candida infection is often associated with this syndrome
- 71. important toraise awareness of these diseases early diagnosis is essential for establishing an appropriate therapeutic regimen A precise molecular diagnosis is not only necessary for initiating the most suitable treatment but it is also important for genetic counseling and prenatal diagnosis
Editor's Notes
- #3 highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens; immune memory, to mount rapid recall immune responses; immunologic tolerance, to avoid immune damage to normal self-tissues.
- #4 Immunity is intrinsic to life and an important tool in the fight for survival against pathogenic microorganisms Innate- Cells of the innate immune system include natural killer cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells Adaptive- these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism
- #5 locations of the sites of infection and the causal microorganisms involved help arrive at a proper diagnoses can also lead to immunopathologic responses such as allergy and autoimmunity
- #11 Hematopoietic stem cells (HSCs) differentiate into common myeloid progenitors (CMPs) and then granulocyte-monocyte progenitors (GM-prog.), which, in turn, differentiate into neutrophils (MB: myeloblasts; Promyelo: promyelocytes; myelo: myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets. Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes. Macrophages in tissues kill using the same mechanism. Following activation by interferon (not shown here), macrophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. SCN, severe congenital neutropenia; WHIM, warts, hypogammaglobulinemia, immunodeficiency myelokathexis; LAD, leukocyte adhesion deficiencies; CGD, chronic granulomatous diseases; MSMD, Mendelian susceptibility to mycobacterial disease.
- #17 can develop bleeding because the 2 integrin in platelets is not functional
- #19 70% of cases are associated with X-linked recessive inheritance versus autosomal inheritance in the remaining 30%. causes deep-tissue bacterial and fungal abscesses in macrophage-rich organs such as the lymph nodes, liver, and lungs
- #21 Macrophage-rich granulomas can often arise in the liver, spleen, and other organs. These are sterile granulomas that cause disease by obstruction (bladder, pylorus, etc.) or inflammation (colitis, restrictive lung disease).
- #23 recessive mutations in genes that encode essential adaptor molecules involved in the signaling pathways of the majority of known Toll-like receptors
- #26 Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give rise to the T cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown. Known T cell effector pathways are indicated, i.e., cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. SCID, severe combined immunodeficiency; ZAP 70, zeta-associated protein deficiency, MHCII, major histocompatibility complex class II deficiency; TAP, TAP1 and 2 deficiencies; Orai1, Stim1 deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of hyper-IgE syndrome; STAT3, autosomal dominant form of hyper-IgE syndrome; CD40L, ICOS, SAP deficiencies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XLP, X-linked proliferative syndromes.
- #28 Lymphocytopenia is strongly suggestive of SCID in more than 90% of cases
- #30 induce premature cell death of lymphocyte progenitors -- results in the absence of B, NK lymphocytes and T cells
- #31 result from mutations in genes encoding proteins that mediate the recombination of V(D)J gene elements in T and B cell antigen receptor genes.
- #32 extremely rare
- #36 consequence of hypomorphic mutations in genes usually associated with SCID or Artemis or IL-7R patients are very fragile, requiring simultaneous anti-infective therapy, nutritional support, and immunosuppression.
- #38 b. caused by a mutation in the calcium channel gene (ORAI-) or its activator (STIM-1)
- #41 AT should be considered in young children with IgA deficiency
- #42 caused by a mutation in the gene encoding the ATM protein With high risk of lymphoma, leukemia and carcinomas
- #44 It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1)
- #45 cytogenetic analysis of multiradial aspects in multiple chromosomes (most frequently 1, 9, and 16)
- #49 Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which give rise to pre-B cells. The B cell differentiation pathway goes through the pre–B cell stage (expression of the heavy chain and surrogate light chain), the immature B cell stage (expression of surface IgM), and the mature B cell stage (expression of surface IgM and IgD). The main phenotypic characteristics of these cells are indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory B cells. PIDs are indicated in the purple boxes. CVID: common variable immunodeficiency.
- #55 Determination of antibody production following immunization (tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens)
- #56 Predispose to severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and dermatomyositis-like disease
- #71 mutations in the autoimmune regulator (AIRE) gene results in impaired thymic expression of self-antigens