1. Lecture Immunodeficiencies

2. Definition Immunodeficiency The inability of the body to produce a sufficient immune response.

3. Primary and Secondary Immunodeficiencies Primary deficiencies – inherited: - inherited dysfunction of genes encoding molecules important for correct immune functioning. Secondary deficiencies – acquired: - acquired damage of molecules and/or cells important for correct immune functions caused by external or internal factors Deficiencies involve: - cellular and humoral immunity - Ag specific or non-specific mechanisms

4. Primary immune deficiences 1) Frequency: more frequent in men 2) Genetics: - point mutations, gene deletions - linked with X chromosome 3) Consequences - absence or dysfunction of a given molecule

5. Clinical manifestations Clinical manifestations of immune deficiencies: 1) Increased susceptibility to infections 2) Autoimmune diseases 3) Lymphoproliferative diseases 4) Allergy 5) Without manifestations – replaced by other immune mechanisms or manifested only under certain conditions

6. Deficiences of innate immunity

7. Deficiencies of Innate Immunity Deficiencies of innate immunity involve: - phagocytosis - complement - combined immunodeficiencies Frequency: frequent, serious medicinal problem

8. Deficiences in Complement Deficiences are rare. 1) Deficiency in C1, C2, C3 and C4 - immune complexes - diseases like Lupus erythematodes - pyogenic infections 2) Defeciency of C1 inhibitor (hereditary angioedema)

9. Deficiences in phagocytosis Number of phagocytes 1. Kostmann syndrome 2. Cyclic neutropenia 3. Reticular dysgenesis

10. Deficiences in phagocytosis Function of phagocytes 1. Chronic granulomatous disease (CGD) defects in NADPH-oxidase, X linked 2. Leukocyte adhesion deficiency (LAD I, II) LAD I > defect in CD18 molecule – diapedesis, without manifestations LAD II > defect in ligands for selectins (sialyl-Le x antigen) 3. Reticular Dysgenesis

11. Deficiences of acquired immunity

12. Deficiencies of Specific Immunity Deficiences of specific immunity involve: - deficiencies of antibody production - T cell dysfunction - combined immunodeficiencies.

13. Antibody deficiencies I - Failure of B cells and Ab production. - Patients suffer from encapsulated microbes. 1) Agammaglobulinemia linked with X chromosome (Bruton) - Mutation in protein kinase C (Btk) encoding signal transduction through BCR - B cells and Ab of all classes totally absent in blood. 2) Selective immunoglobulin deficiencies (dysimmunoglobulinemia) - Partial or total absence of some isotypes - The most frequent is IgA deficiency. In mucosa, partially supplied by IgM, in lower respiratory by IgG. - Without manifestations or higher sensitivity to respiratory infections, allergy, autoimmunity (and tumors?)

14. Antibody deficiencies II 3) Selective deficiency of IgG subclasses Deficiency of IgG subclasses also in combination with IgA deficiency 4) Selective deficiency of Ab specific for certain Ag Deficiency of Ab against lipopolysaccharides 5) Transient hypogammaglobulinemia of infancy Delayed onset of IgG production in newborns. Spontaneous recovery.

15. Common variable immunodeficiency ( CVID ) Definition Mixed group of diseases in which the production of antibodies is defective. Increased risk of life-threatening infections.

16. COURSE Clinically, CVID may resemble HIV infection, as it may cause weight loss swelling of the lymph nodes diarrhea lymphoma idiopathic thrombocytopenic purpura CVID

17. Symptoms : INFECTIONS Acute, recurring bacterial infections, including pneumonia, bronchitis and sinusitis. infections from Hemophilus spp., Streptococcus pneumoniae, herpes, GI-tract infectionsHemophilus spp. Streptococcus pneumoniae Children with CVID are susceptible to otitis media, and infections may develop in the joints, bones, skin and parotid glands. AUTOIMMUNITY Autoimmune diseases (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis, celiac disease)autoimmune hemolytic anemiaidiopathic thrombocytopenic purpurarheumatoid arthritisceliac disease CANCER increased risk cancer (non-Hodgkin lymphomas and adenocarcinomas)

18. Aethilogy homozygous null mutations in ICOS gene => panhypogammaglobulinemia a susceptibility locus exists in the class III MHC region Cause of CVID is uncertain and may vary among patients. in 10% of cases familiarity exists CVID

19. Pathogenesis: Many patients with CVID have near-normal numbers of antibody- bearing B cells, but these fail to mature into plasma B cells -> low IgG, IgA and IgM (or undetectable amounts of the immunoglobu- lins). Other CVID patients have low numbers of B cells. Some have abnormalities of T-cells (ICOS gene). CVID

20. Epidemiology: CVID is the most common clinically significant primary immunodeficiency disease (several thousand patients) It occurs equally in both sexes. CVID may become apparent in infancy or as late as the 5th decade of life. The average age of onset is 27 years.

21. CVID Treatment - prophylactic administration of human immunoglobulin every 3 weeks throughout the patient's life, along with - systemic antibiotics as necessary for the management of concomitant infections.

22. T cell immunodeficiences Distinguished as: severe combined disorders - T cell totally absent diseases caused by functionally abnormal T cells

23. T cell immunodeficiences Severe combined immunodeficiency - The most serious primary deficiency - Manifested early after delivery – viral infections, intracellular microbes, opportunistic microbes - Lethal without treatment - Aethiology: heterogeneous, increasing number of diseases

24. T cell immunodeficiences 1.Adenosin deaminase deficiency 2.Severe Combined Immunodeficiency (SCID)Severe Combined Immunodeficiency (SCID) 3.Reticular dysgenesis

25. Combined immunodeficiences 1. Ag presentation6. Omen Syndrome 2. Activation of T cells7. Hemophagocytic Lymphohistiocytosis 3. Hyper IgM syndrome8. X-linked Lymphoproliferative Syndrome 4. Wiscott-Aldrich syndrome 9. Familiar Autoimmune Lymphoproliferative Syndrome 5. Chediak – Higashi syndrome

26. Other Deficiences Hyperimmunogamaglobulinemia (Job syndrome) Mucocutaneous candidosis Ataxia teleangiectasia

27. Secondary Immunodeficiences Deficiences are caused by 1) Infections (HIV) 2) Metabolic disease (diabetes melitus, kidney and liver dysfunctions 3) Nutrition (proteins, vitamins, minerals) 4) Treatment procedures (splenectomy, chemotherapy...)

28. Autoimmunity Immunopatologic reactions Immune mechanisms recognize self antigens and destruct self cells and molecules

29. Autoimmunity Mechanisms (intrinsic factors): 1.) Association with certain MHC molecules >>> HLA-B27 -Bechterev disease 2) Deficiency in cytokines 3) Deficiency in genes which regulate apoptosis (Fas, FasL, Bcl-2) 4) Association with immunodeficiencies 5) Polymorphism of TCR genes and H chains of Immunoglobulines 6) Hormonal effects

30. Autoimmunity Mechanisms (external factors): Infections, stress, drugs, UV radiation 1) Cryptic Ag (intracellular) 2) expression of MHCII - inflammatory cytokines – presentation of Ag, which are normally not accessible 3) :”Molecular mimicry” similarity of self and microbial antigens 4) Microbial superantigenes

31. Autoimmunity Mechanisms (external factors): Infections, stress, drugs, UV radiation 1) Cryptic Ag (intracellular) 2) expression of MHCII - inflammatory cytokines – presentation of Ag, which are normally not accessible 3) :”Molecular mimicry” similarity of self and microbial antigens 4) Microbial superantigenes

32. Autoimmunity Lupus erytematodes Reumatoid artritis Sjörgen disease Systemic sclerodermitis Connective tissue disease Antiphospholipid disease Vasculitis

33. Autoimmunity Hashimoto thyroiditis Graves-Basedow disease (TSH) Diabetes melitus Myasthenia gravis (acetylcholine receptors) Hematological (cytopenias) Skin autoimmune reactions