Dr. Gülderen Yanıkkaya Demirel IMMUNODEFICIENCIES Dr. Gülderen Yanıkkaya Demirel

What is Immunodeficiency? A failing of one or more of the body’s defensive mechanisms resulting in morbidity or mortality. Any part of the immune system can be deficient cells, proteins, signalling mechanisms……. The body is susceptible to infection by organisms that meet with little or no resistance. Or, in certain cases, other homeostatic systems in the body will be disrupted by the defect. Severity is variable. May be Primary or Secondary.

IMMUNODEFICIENCIES Primary (inherited) Secondary (to some other) Physiological

Immunodeficiency (Defect in one or more components of immune system) Types: Primary: Mutation in genes controlling immune system (e.g. Recurrent, severe infection in children) Secondary: Acquired as a consequence of other diseases or environmental factors (e.g. infection, malignancy, aging, starvation, medication, drugs)

Clinical features associated with immunodeficiency Feature frequency present and highly suspicious: Chronic infection Recurrent infection (more than expected) Unusual microbial agents Incomplete clearing of infection Incomplete response to treatment

Clinical features associated with immunodeficiency Feature moderately suspicious Diarrhea (chronic) Growth failure Recurrent abscesses Recurrent osteomyelitis Feature associated with specific immunodeficiency disorder Telangiectasia Partial albinism

CLASSIFICATION of PRIMARY IMMUNDEFICIENCIES Combined T cell and B cell immunodeficiencies Predominantly antibody deficiencies Other well defined immunodeficiency syndromes Diseases of immune dysregulation Congenital defects of phagocyte number, function or both Defects in innate immunity Autoinflammatory disorders Complement deficiencies

Primary Immunodeficiencies Stem Cell Reticular Dysgenesis Lymphoid Progenitor Myeloid Progenitor Severe combined Immunodeficiency SCID Congenital Agranulocytosis Pre-B Monocyte Pre-T Neutrophil x-linked agglobulinemia xLA Mature B Thymus Leukocyte Adhesion Deficiency DiGeorge Syndrome D Chronic Granulomatous Disease (x or D) Mature T Plasma Cell Memory B WAS Common Variable Hypogglobulinemia / x-linked hyperIgM syndrome/Selective Ig deficiency WAS=Wiskott- Aldrich Syndrome x Bare Lymphocyte Syndrome

Phagocyte Deficiencies: Chronic granulomatous disease (CGD) Leukocyte adhesion deficiency (LAD I) Chediak- Higashi syndrome IL-12 / IFN pathway deficiencies Chronic or cyclic neutropenia

Leucocyte Adhesion Defect (LAD)

Defects in T cell-B cell interactions Btk=Bruton tyrosine kinase Defect (XLA) IL-2Rg defect IL-2Rg IL-2, 4, 7, 9, 15 B J Btk XHM CD40 CD40L JAK3 defect Ag JAK-3 Ag RAG 1/2 RAG1/2 MHC II TCR Ig Bare Lymphocyte Syndrome (MHC II- ve) CD4 T cell B cell RAG=Recombinase activating gene defect (SCID) JAK=Janus kinase

Adaptive Immunity Deficiency T cell deficiency Susceptible to intracellular bacterial infection Susceptible to viral, parasitic and fungal infection B cell deficiency Susceptible to extracellular bacterial infection Severe Combined Immunodeficiency Disease (SCID) T and B cell functions defective Usually fatal Transplacental/milk transmission of Abs TCR gene rearrangement lacking Myeloid and erythroid components intact

Ig Levels vs Age

Overview of B-Cell Development

Hyper IgM syndrome

Serum levels of immunoglobulin in Hyper IgM syndrome IgG↓ IgM ↑↑ IgA↓ IgE↓

Hyper IgM syndrome Defect in CD40 ligand T cell B cell Ig Class switch

Selective IgA Deficiency Selective IgA deficiency is the most common ID disorder. The prevalence is about 1:700. Pathogenesis : block in B cell differentiation is due to intrinsic B cell defect or abnormal T cell help such as production of cytokine (TGF-B,IL-5) or in B cell responses to these cytokines.

IgA Deficiency Clinical feature: Recurrent sinopulmonary infection, gastrointestinal disorders, allergy, cancer and autoimmune disease. IgA Deficiency and genetic factors: association with HLA-A2, B8 and DW3 or A1 and B8. IgA Deficiency and drug. Serum IgA<5mg/dl but normal IgM and IgG Immunopathogenesis :arrest in the B cell differentiation.

Selective IgG subclass deficiency Total serum IgG levels are normal One or more subclasses are below normal. IgG3 deficiency is the most common subclass in adults. IgG2 deficiency associated with IgA deficiency in children. Pathogenesis: abnormal B cell differentiation. Some individual have recurrent bacterial infection.

Nude Athymic mouse

Secondary or Acquired Immunodeficiencies Agent-induced immunodeficiency: e.g. infections, metaboic disturbance, trauma, corticosteroids, cyclosporin A, radiation, chemotherapy Acquired Hypogammaglobulinemia (Low levels of Ig; recurrent infections; treat with Ig)

Secondary Immunodeficiency - Infection - Renal failure, or protein losing enteropathy Leukaemia or Lymphoma Myeloma Extremes of age - Certain Drug Therapies

MALNUTRITION Most common cause of secondary immune deficiency. Protein-calori malnutrition can lead to abnormalities of T cells, B cells and phagocytes Atrophic and fibrotic thymus Reduced lymphocyte proliferation in response to antigens.

INITIAL SCREENING for ID’s Blood Count Quantitative Immunoglobulins Antibody responses to previous vaccines Isoagglutinin (Anti-A and Anti-B) titers Total hemolytic complement Infection Evaluation (ESR, appropriate cultures, X-rays)

Human Immunodeficiency Virus Discovered in 1983 Luc Montagnier and Robert Gallo Retrovirus HIV-1 and HIV-2 Patients with low CD4+ T cells Homosexual; promiscuous heterosexual, i.v. drug users; transfusion; infants born to infected mothers Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium, etc. Kaposi sarcoma

Kaposi Sarcoma

Acquired Immunodeficiency Syndrome (AIDS) Structure of HIV-1 gp120 env gp41 Protease Envelope Reverse Trascriptase pol Integrase Matrix (p17) gag Capsid (p24) Genome

HIV Infection Coreceptors: Chemokine receptors T cell-tropic (Syncitium-inducing) gp120 CXCR4: SDF1 (Stromal cell derived factor) CD4 ssRNA Macrophage-tropic (Nonsyncitium inducing) Provirus CCR5: RANTES (regulated on activation, normal T cell expressed and Secreted), MIP1a, MIP1b (Macrophage Inflammatory Protein) Reverse transcriptase dsDNA

Serological Profile Kuby, 2007

Host Factors influencing course Transmission of HIV Sexual contact Breast feeding Transfusion During birth Sharing needles Resistance to HIV in individuals CCR5D32 Some HLA types (HLA-A2 are resistant; HLA-B35 are susceptible)

Virus-induced effects on immune cells Th Cells Initially control viral load Destruction of infected Th cells by CTL Cytopathic virus Anergy of surviving Th cells CTL gp120 specific CTL Virus mutation induces resistance to CTL Lack of Th affects CTL activation Resistance to CTL by downregulation of class I MHC on target cells Ab Develops after 3 weeks Virus Agic variability Non-neutralizing. Thus, ineffective

Immunomodulation HAART + IL-2 (To reconstitute the immune system) Chemokine receptor inhibitors Vaccines: Proteins, DNA, subunit and recombinant virus (SIV-HIV chimeric virus ) Problems HIV-1 inf. -> AIDS in the presence of Abs Low immunogenicity Destruction of CD4+ T cells by vaccine Integration of virus in host genome Instability of HIV-1 genome High rate of virus replication (109 viruses/day) Live attenuated or heat killed organism (vaccinia virus carrier for HIV proteins) Route of exposure (Rectal or vaginal challenge) Lack of animal models and in vitro testing system

Summary Primary immunodeficiencies are inherited They can affect hematopoietic stem cells, lymphoid or myeloid cells. Secondary immunodeficiencies are due to infections, aging, cancer or chemical exposure HIV affects immune system by eliminating CD4+ T cells Vaccine development has been hindered by lack of an experimental model, antigenic variation, etc.