2. PRIMARY (INBORN) AND SECONDARY (ACQUIRED) IMMUNODEFICIENCIES (ID) LECTURE 12 Jan Żeromski 2007/2008

3. PRIMARY ID: GENERAL DATA Relatively infrequent (average 1 per 100.000) Lack or improper function of one or more elements of immune system Increased susceptibility for infections but other follow ups include autoimmunity, hypersensitivity and malignancy Are hereditary, with familiar trait, often linked to X chromosome

4. PRIMARY IDs ( ACCORDING TO WHO-1999) Combined Other well characterized Syndromes of chromosomal instability Appear with other inborn defects Other Disturbances of antibody biosynthesis Defects of fagocytosis Deficits of complement components Co-existing with defects of lymphoproliferation

5. SEVERE COMBINED IMMUNODEFICIENCY (SCID) DISEASEMECHANISM 1.Severe (T-B-SCID) Reticular dysgenesis Deficiency- RAG1,RAG2 Defects of stem cells and genes for Ig and TCR (recombinations) 2.Defective purine metabolism deficiency of ADA and PNP Toxic metabolites for lymphocytes 3.Lack of expression of MHC antigens, class I and/or class II Lack of gene transcription for MHC and TAP proteins 4.Hyper IgM syndromeLack of CD40L signal from T to B cell 5.CD3 deficiencyDefect of CD3-TCR proteins 6.Omenn syndrome (SCID with hypereosinophilia) RAG1 and RAG2 mutations

6. COMBINED SCID Disease Severe (T-B-SCID) Reticular dysgenesis Deficiency-RAG1,RAG2 Defective purine metabolism deficiency of ADA and PNP Lack of expression of MHC antigens, class I and/or class II Mechanism Defects of stem cells and genes for Ig and TCR (recombinations) Toxic metabolites for lymphocytes Lack of gene transcription for MHC and TAP proteins

7. COMBINED SCID-contd. Disease Hyper IgM syndrome CD3 deficiency Omenn syndrome (SCID with hypereosinophilia) Mechanism Lack of CD40L signal from T to B cell Defect of CD3-TCR proteins RAG1 and RAG2 mutations

8. B CELL DEFICIENCIES X-linked agammaglobulinemia (Bruton disease) – lack of Btk kinase necessary for B cell formation; Common variable ID(CVID) – defects of T lymphocyte signaling to B cell; IgA deficiency defect of Ig class switch; Selective Ig subclass deficiency; Transient hypogammaglobulinemia of infants – maturation defect of Th cell function.

9. OTHER WELL CHARACTERIZED SYNDROMES OF ID 1. Wiskott-Aldrich syndrome (WAS) mutation of Xp11.22 gene encoding WASP protein results in defects of cytoskeleton of T cells (faulty collaboration among T and B cells) Symptoms: thrombocytopenia, eczema, infections, variations in Ig levels, risk of lymphoma

10. OTHER WELL CHARACTERIZED SYNDROMES OF ID (cont.) 2. DiGeorge syndrome (DGS) congenital defect in the organs derived from third and fourth pharyngeal pouches (lack of thymus and parathyroids, malformations of the heart and/or aortic arch) Symptoms: viral and fungal infections, neonatal tetany, distinctive facial features

11. SYNDROMES OF CHROMOSOMAL INSTABILITY 1.Hereditary ataxia-teleangiectasia (AT) lack of ATM kinase involved in repair of double- strand breaks of DNA; defects of cell cycle control Symptoms: as in the name, severe sinus and lung infections, T cell and B cell deficiencies 2.Nijmegen breakage syndrome (NBS) defects of rearrangement of Ig genes, faulty DNA reparation (mutation of NBS1 gene) Symptoms: microcephaly, developm. retardation, Ig deficiencies,T cell-lymphocytopenia

12. HEREDITARY PHAGOCYTE FUNCTION DEFICIENCIES 1. Chronic granulomatous disease (CGD) comprises a group of 4 disorders with a common phenotype. Deficient superoxide (0 - 2 ) generation via the phagocyte NADPH oxidase Symptoms: recurrent infections, abscesses, granuloma formation 2. Chediak-Higashi syndrome defect of lysosome formation; mutation of CHS1 gene Symptoms: albinism, infections, photophobia, pancytopenia, lack of NK cell activity

13. DISORDERS OF PHAGOCYTE NUMBER 1.Kostman syndrome infantile agranulocytosis Symptoms: severe infections, sepsis already at the newborn period 2.Cyclic neutropenia periodic (every 2-3 weeks) fall of neutrophil number 3.Shwachman syndrome neutropenia, defects of chemotaxis and bacterial killing 4.Chronic mild familiar neutropenia

14. HEREDITARY LEUKOCYTE FUNCTION DEFICIENCIES Leukocyte adhesion deficiency (LAD) LAD1 defect of CD11/CD18 integrin  chain (CD18) biosynthesis. Symptoms: recurrent necrotizing infections, failure to form pus LAD2 defect of sialyl Lewis (CD15s) ligand for the selectin family. Symptoms: growth and mental retardation, hypotonia, seizures, persistent periodontitis

15. Leukocyte adhesion deficiency (LAD-1) Is due to integrin gene defects – deficiency of CD18, forming 3 important molecules: CD18/CD11a (LFA-1), CD18/CD11b (Mac-1 or CR3, and CD18/CD11c (CR4 or p150,95) These molecules are expressed on different classes of leukocytes and mediate their adhesion to endothelium

16. Leukocyte adhesion deficiency (LAD-1) - 2 Leukocytes show defective chemotaxis and adherence, T lymphocytes and NK cells have impaired cytotoxic activity, Infants show delayed umbilical cord separation, persistent leukocytosis, destructive peridontitis, recurrent infections (S. aureus, Pseudomonas, Klebsiella)

17. LAD type 2 Leukocytes cannot roll on endothelial surface Rolling is due to selectins, which react with glycoproteins containing fucosylated shugars Genetic defect in conversion of mannose to fucose results in failure of normal synthesis of these selectin ligands, such as blood group sialyl Lewis x Sialyl Lewis x is defective (hypofucosylated)

18. LAD type 2 - 2 Leukocytes cannot roll, so their export from vessel lumen is considerably retarded Clinical features: growth and mental retardation,strabismus, dysmorphia, persistent peridontitis Leukocytosis in absence of infection Wound healing is not impaired

19. DEFICIENCIES OF COMPLEMENT COMPONENTS – 1% of ID 1.Deficits of classical pathway of activation 2.Deficits of C3 and of proteins of alternative pathway 3.Deficits of components of lectin pathway 4.Deficits of membrane attack complex (MAC) C5 –C9 5.Deficits of C1 inhibitor

20. OTHER PRIMARY ID 1.Job syndrome (hyper IgE): - faulty chemotaxis, high IgE Symptoms: recurrent infections, severe eczema, facial and skeletal abnormalities, eosinophilia 1.Duncan disease: - X-linked lympho-proliferative syndrome 2.Failure of tubercle bacilli killing: - defect of IFN-  R and /or IL-12R 3.Chronic muco-cutaneous candidiasis 4.T CD4+ cell lymphopenia

21. TEN WARNING SYMPTOMS OF ID 1.Six or more infections per year 2.Two or more severe sinusitis per year 3.Antibiotic treatment lasting 2 months or longer without visible effect 4.Two or more pneumonias per year 5.Retardation of growth and development of child

22. TEN WARNING SYMPTOMS OF ID (CONTINUED) 6.Recurrent deep skin or organ abscesses 7.Persistent mycosis of oral cavity and skin in a child >1 year old 8.Necessity of long lasting application of intravenous antibiotics to control infection 9.Two or more severe infections such as encephalitis, osteitis, dermatitis, myositis, sepsis 10.Family history indicating primary ID

23. SECONDARY ID - CAUSES 1.Glycocorticoids: lympho- and monocytopenia, inhibition of T cell activation, IL-1 and TNF synthesis; 2.Cytostatics: act mainly on DNA and its synthesis; 3.Malnutrition; 4.Deficits of elements (selene, magnesium, iron etc.); 5.Deficits of vitamins (A, C, D, B6, folic acid); 6.AIDS; 7.Other viral infections (mainly of herpes group).

24. ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) – GENERAL DATA Etiology: HiV-1 and HIV-2 retrovirus (RNA) M-tropic and T-tropic viruses (the latter worse) T-tropic form syncytia from infected and non-infected cells, what results in rapid cell destruction HIV receptors: CD4 and chemokine receptors (CCR5, CCR3, CXCR4) Main reservoir of virus – lymphatic tissue

25. AIDS PATHOGENESIS Early period: fall of CD4+ cells, viremia, lack of immune response; Fall of viremia, an increase of TCD8+ cell number able to kill infected cells; Appearance of anti-HIV antibodies; Growth of virus mutagenicity; Dysfunction and decline of Th1 CD4+ cell number with parallel increase of Th2 cells; Development of symptomatic AIDS.

26. THANK YOU GOOD LUCK