By: Oki Suwarsa, dr, MKes, SpKK(K)
IMMUNODEFICIENCY By: Oki Suwarsa, dr, MKes, SpKK(K) IMMUNODEFICIENCY Risk of opportunist infection & tumors
Divided in two types: Primary immunodeficiency : Relatively rare Genetic basis Secondary immunodeficiency: More common Caused by lesion outside the immune system Repeated/unusual infection immunodeficiency
Type of infection cause & degree of immunodeficiency Repeated bacterial infection defective antibody Respiratory infection caused by Pneumococcus or Haemophilus spp. bronchiectasis Gram - & fungi abnormal phagocytes Meningococcal meningitis defective complement Defective T cells or macrophages infection of intracelullar organisms : protozoa, virus, intracellular bacteria (mycobacteria & salmonella) Reactivation of herpes virus infection T cell immunodeficiency
Herpes virus induce tumors, kaposis sarcoma, non-Hodkins lymphoma T cell dysfunction the degree of T cell immunodeficiency pattern of mycrobial infection Mild Mycobacterium tuberculosis (virulent) spreads outside the lungs Severe infection of mycobacterium of low virulence, found in environment (Mycobacterium avium) or vaccine Features of immunodeficiencies affecting T & B lymphocytes Immunodeficiency caused by defect in B & T cells maturation Immunodeficiency caused by defects in B & T cell activation Defect of lymphocyte maturation Defect in lymphocyte activation PRIMARY IMMUNODEFICIENCY
Infection Mutation Polymorphisms Polygenic Tumors Gene therapy Immunoglobulins Causes of primary immunodeficiency
Mutation : Rare, affect any part of immune system Severe disease Polymorphisms : Common traits, affect any part of the immune system Moderate increased risk of infection Polygenic disorders : Relatively common, affect mainly antibody Repeated or unusual infection suggests immunodeficiency Defects in innate immune system are characterized by extracellular pathogen infections Mutations and immunodeficiency
12 important mutations immunodeficiency > Mutation severe combined immunodeficiency (SCID) Affecting both B & T cells Autosomally inherited RAG deficiency X linked -chain deficiency & hyper-IgM syndrome The Di George syndrome translocated of chromosome 22, not inherited T cell defects Polymorphisms & immunodeficiency
Polymorphisms : alleles of the same gene occurring at a single locus in 1% population HLA alleles polymorphic affect the outcome of infection (hepatitis B, hepatitis C & HIV) Polymorphisms promoter of TNF genes risk cerebral malaria & septic shock Polymorphisms chemokines & their receptors risk HIV Polymorphisms in MBL & complement risk infections Polygenic disorder Caused by interaction of several genes with environmental factors Common variable immunodeficiency (CVID) & deficiency of IgA & IgG common polygenic disorder, affecting Ab IgA deficiency 1:600 people Celiac disease more common in IgA deficiency CVID commonest immunodeficiency treatment CVID recurrent infection of respiratory tract, start in early adult Autoimmunity is common in CVID & frequently includes pernicious anemia & thyroid disease, arthritis & immune thrombocytopenia Diagnosis SCID should be considered if:
Unusual or recurrent infection Failure to thrive & diarrhea Unusual rashes A family history of neonatal death or of consanguinity A very low total lymphocyte count (below 1 x 109/L) Avoid serious infection:
Avoid live vaccine : BCG, measles, mumps, rubella & polio Use prophylaxis against opportunist infections : Pneumocystis carinii pneumonia Suspect SCID exclude HIV refer to spesialist to confirm diagnosis definitive treatment (often bone marrow transplant) Diagnosis Chronic or recurrent bacterial respiratory infection Indication for testing measure of IgG, IgA & IgM If total Ig normal measure IgG subclasses & spesific Ab against Haemophilus & Pneumococcus spp. If all test normal check complement or neutrophil function Patient with atypical viral, protozoal or mycobacterial infection rule out T cell immunodeficiency Patient with suspected cellular immunodeficiency measure lymphocyte numbers Genetic testing PCR Sepuluh tanda imunodefisiensi
Dua atau lebih gejala dalam satu tahun Jeffrey Modell Foundation Empat atau lebih infeksi telinga dalam setahun
Dua atau lebih infeksi sinus berat dalam setahun Pada bayi terjadi kegagalan peningkatan berat badan dan gagal tumbuh Dua bulan atau lebih pemakaian antibiotik dengan sedikit efek Dua episode atau lebih pneumonia dalam setahun Kandidiasis persisten di mulut atau di mana saja usia >1 tahun
Abses berulang pada kulit dan organ dalam Riwayat keluarga dengan imunodefisiensi primer Kebutuhan penggunaan antibiotik intravena untuk mengatasi infeksi Dua atau lebih infeksi dalam termasuk septikemia Treatment Aim of treatment prevent infection
Mild cases prophylactic antibiotics More severe Ab deficiency immunoglobulin replacement therapy (intravenous or subcutaneus) T cell deficiency bone marrow transplant (BMT) If BMT isnt option gene therapy Congenital disorders of innate immunity SECONDARY IMMUNODEFICIENCY
Infection HIV Stress Nutrition Tumors vaccines Immunomodulation Extremes of age Drugs Secondary immunodeficiency
Can be severe : HIV infection Myeloma Some drug treatments Acquired immunodeficiencies HIV Infection Most important caused of secondary immunodefiency affecting over 30 million people Monitoring infection : Immunological monitoring CD4 cell counts form part of assessment schemes for progression of HIV infection (CDC) CD4 < 200 /l high risk PCP prophylaxis CD4 < 100 /l consider CMV & atypical mycobacteria Virological monitoring viral load HIV infection and viral mutations Structure of HIV-1 HIV-1 genome HIV life cycle Mechanism of HIV entry into a cell Progression of HIV infection Clinical course of HIV disease Clinical features of HIV infection Cellular reservoirs of HIV Candidate HIV vaccines Other secondary immunodeficiency
Nutrition Deficiency of zinc & magnesium impairs cell mediated immunity, particularly TH1-cytokine secretion Loss of fat low levels of leptin mild immunodeficiency Physiological stress The immune system in the first year of life Spesific immune system remain immature Neonates have high number of T cells all naive not respond to Ag Transient hypergammaglobulinemia of infancy delay in maturation of Ig, especially IgG2 (maternal Ab ) Other secondary immunodeficiency
The aging immune system Elderly thymic function more infection Miscelaneous factors B cell malignancy Myeloma & chronic lymphocytic leukemia Ab common caused of immunodeficiency in elderly Thymoma rare tumor cause immunodeficiency Other secondary immunodeficiency
Drugs Common caused Eliminating offending drug improve immune response Immunosupression side effect steroids, cytotoxic drugs & immunosupressive regimens Kidney disease Nephrotic syndrome Renal protein loss blood level of IgG & IgA, normal IgM Severe diarrhea lost igG via the gut Renal failure & diabetes secondary phagocyte defect Infection Malaria & congenital rubella Ab deficiency Measles defects in cell mediated imunity could reactivate tuberculosis Combined immunodeficiency
Syndrome: Wiskott-Aldrich syndrome Trias: eksim, trombositopenia, imunodefisiensi Ataksia-teleangiektasia Ataksia serebelar, teleangiektasia okulokutaneus Sindrom DiGeorge Delesi kromosom 22q11 Malformasi jantung, hipotiroid, hipokalsemi, wajah dismorfik, gangguan perkembangan timus Thank You