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Inmunodeficiencia

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Inmunodeficiencia

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Inmunodeficiencia

  1. 1. Objectives Definition Primary Immunodeficiencies Characteristics Types of primary immunodeficiency disorders Mode of inheritance Diagnosis and Treatment
  2. 2. Immunodeficiency Defect in 1 or more components of immune system Types: Primary or Congenital: Born with the immunodeficiency Inherited (Mutation in gene controlling immune cells) Susceptible to recurrent, severe infection; starting in children Cannot recover without treatment >150 immunodeficiency disorders
  3. 3. Hematopoiesis Progenit or Progenit or
  4. 4. Hematopoietic Stem Cell (HSC) deficiency HSC are multipotent (differentiate into all blood cell types) Self renewing cells Lineage negative (mature B/T cell, granulocyte, Mφ markers absent) CD34+, c-Kit+, Stem cell Ag (Sca-1+) on cell surface Defect in HSC results in Reticular Dysgenesis Affects development of all leukocytes Patients are susceptible to all infections (bacterial, viral, parasitic and fungal) Fatal without treatment Treated with bone marrow or HSC transplantation
  5. 5. TCR Allogeneic BM/HSC Transplantation HSC Thymus Thymic Stromal Cells MHC T cell MHC T cell MHC-matched for atleast1-2 alleles T cell depleted TCR T cells
  6. 6. Hematopoiesis Progenit or Progenit or
  7. 7. Myeloid Progenitor Cell Differentiation Defect Myeloid Progenitor Cells develop into neutrophils and monocytes Defect in differentiation from myeloid progenitor cells into neutrophils results in Congenital Agranulocytosis Recurrent bacterial infections seen in patients Treated with granulocyte-macrophage colony stimulating factor (GM-CSF) or G-CSF
  8. 8. Defective Neutrophils Patients have neutrophils that are defective in production of reactive oxygen species that is responsible for killing of phagocytosed microrganisms. Nitroblue tetrazolium test: reduction by superoxide (- ve) This results in accumulation of granulocytes, Mφ and T cells forming granulomas. These patients suffer from Chronic Granulomatous Disease. Have recurrent bacterial infections Commensals become pathogenic X-linked or autosomal recessive
  9. 9. Inheritance22 pairs of autosomes and 1 pair of sex chromosomes (X and Y) Autosomal recessive (most AA normal; Aa carrier; aa affected) Autosomal dominant (Aa affected; aa is normal) X-linked (XX carrier daughter; XY affected son) Carrier x Carrier Mother Father Aa Aa Normal x Affected Mother Father aa Aa Carrier x Normal Mother Father Xx XY Autosomal Recessive Autosomal Dominant X-linked
  10. 10. Leukocyte Adhesion deficiency Adhesion molecule (e.g.CD18) may be lacking on T cells and monocytes. Autosomal recessive Results in defective extravasation Recurrent infections Impaired wound healing Treated with BM (depleted of T cells and HLA matched) transplantation or with gene therapy
  11. 11. Hematopoiesis Progenit or Progenit or
  12. 12. Defect in Lymphoid Progenitor Results in Severe Combined Immunodeficiency (SCID) Lack T, B and/or NK cells Thymus does not develop Myeloid and erythroid cells are normal. Generally lethal Susceptible to bacterial, viral and fungal infections. In infants, passively transferred maternal Abs are present. Live attenuated vaccines (e.g. Sabin polio) can cause disease.
  13. 13. Types of SCID RAG-1/2 (Recombinase activating gene) deficiency: Required for TCR and Ig gene rearrangement IL-2R gene defect Adenosine deaminase (ADA) deficiency Adenosine Inosine Uric acid T, B and NK cell deficiency due to toxicity of accumulated metabolites First successful gene therapy done in patient T cells/ NK cells IL-2 receptor IL-2 TCR T cells B cells Ig ADA
  14. 14. DiGeorge syndrome
  15. 15. Precursor T cell differentiation defect Athymic - DiGeorge Syndrome Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T regulatory (Treg) cells B cells are present but T-dependent B cell responses are defective Anti-viral and anti-fungal immunity impaired Developmental defect in the 3rd and 4th pharyngeal pouch  Results in facial defect and congenital heart disease Treated with thymic transplant Autosomal dominant trait
  16. 16. Nude Athymic mouse nu/nu gene (autosomal recessive) Hairless Should be maintained in pathogen-free environment T helper cell defect Results in impaired cytotoxic T cell activity and Th- dependent B cell responses due to Th cell defect Accept xenografts
  17. 17. Hyper IgM Syndrome Absence of Igs and B cells Arrest at Pre-B cell stage (H-chain rearranged not L chain) Deficiency in IgG, IgA and IgE Increased IgM in serum B cells express IgD and IgM on membrane X-linked Recurrent infections e.g. IgA deficiency Due to defect in isotype switching Recurrent respiratory, gastrointestinal and/or genitourinary infection Selective Ig class deficiency X-linked Agammaglobulinemia (x-LA) Pre B cells Mature B cells x-LA Proliferation Differentiation Isotype switchingCVD IgA def. Plasma cells IgM
  18. 18. Common Variable Immunodeficiency B cells are normal Defect in maturation to plasma cells Decreased IgM, IgG and IgA or only IgG and IgA Susceptible to bacterial (e.g. pneumococci) infections Low Ab titers against DPT or MMR Vaccines Usually not detected in children because of maternal Abs Also called Late-onset hypogammaglobulinemia, Adult-onset agammaglobulinemia or Acquired agammaglobulinemia Ig replacement therapy and antibiotics Pre B cells Mature B cells x-LA Proliferation Differentiation Isotype switchingCVD IgA def. Plasma cells IgM
  19. 19. Other Immunodeficiencies Bare lymphocyte syndrome: Lack MHC class II on B cells, macrophages and dendritic cells Complement Deficiency
  20. 20. x-linked aγglobulinemia xLA DiGeorge Syndrome d Common Variable Hypoγglobulinemia / x-linked hyperIgM syndrome/Selective Ig deficiency Primary ImmunodeficienciesStem Cell Myeloid Progenitor Lymphoid Progenitor Neutrophil Monocyte Pre-B Pre-T Mature B Plasma Cell Memory B Thymus Reticular Dysgenesis Severe combined Immunodeficiency SCID Congenital Agranulocytosis Chronic Granulomatous Disease (x or r) Bare Lymphocyte Syndrome Mature T
  21. 21. Adaptive Immunity Deficiency T cell deficiency Susceptible to intracellular bacterial infection e.g. Salmonella typhi, Mycobacteria  Susceptible to viral, parasitic and fungal infection B cell deficiency Susceptible to extracellular bacterial infection e.g. Staphylococcal infection

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