Immunodeficiency

Objectives Definition Primary Immunodeficiencies Characteristics Types of primary immunodeficiency disorders Mode of inheritance Secondary Immunodeficiency Human Immunodeficiency Virus Immune response to HIV

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 and severe infections Start in childhood Cannot recover without treatment Secondary or Acquired: As a consequence of other diseases, drug therapy or environmental factors (e.g. infection, malignancy, aging, malnutrition, drugs, trauma, radiation, surgery). Prototype - Human Immunodeficiency Virus s

Inheritance of Primary Immunodeficiency disorders 22 pairs of autosomes and 1 pair of sex chromosomes (X and Y) Follow the Mendelian laws of inheritance

Examples of Inheritance Patterns of Primary Immunodeficiency Carrier x Carrier Mother Father Aa Aa Normal x Affected Mother Father aa Aa Carrier x Normal Mother Father XX XY M F X Y XX Normal XY Carrier Affected Autosomal Recessive Autosomal Dominant X-linked Heterozygous are not affected Heterozygous are affected 50% of males are affected

Hematopoiesis Progenitor Progenitor

Hematopoietic Stem Cell (HSC) deficiency HSC are multipotent (differentiate into all blood cell types) Self renewing cells Defect in HSC results in immunodeficiency known as Reticular Dysgenesis Affects development of all leukocytes Patients are susceptible to all infections (bacterial, viral, and fungal) Fatal without treatment Treated with bone marrow or HSC transplantation

Defects in Lymphoid Lineage Progenitor Progenitor

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.

Bubble Boy David Vetter (1971-84; SCID patient died of EBV-induced lymphoma and not due to GVHD following BM transplantion from sister) Ted DeVita (1962-80) – Aplastic anemia Died of iron overload due to repeated transfusions

Types of SCID TCR Ig B cells T cells T cells/ NK cells IL-2 RAG-1/2 (Recombinase activating gene) deficiency: Required for TCR and Ig gene rearrangement. lack T and B cells but have NK cells IL-2R γ gene defect (X-linked) 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 (Ashanti DeSilva treated at NIH in 1990) TCR Ig B cells T cells T cells/ NK cells IL-2 receptor (α,β and γ common chain). γc chain common for IL-2, 4, 7, 9, 15 IL-2 ADA

Defect in T cell development Progenitor Progenitor

DiGeorge syndrome

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, congenital heart disease, parathyroid defect Treated with MHC-matched thymic epithelial cell transplant Autosomal dominant trait

Defects in B cell development Progenitor Progenitor

Hyper IgM Syndrome (HIgM) X-linked Agammaglobulinemia (x-LA) Absence of Igs and B cells Arrest at Pre-B cell stage (H-chain rearranged but not L chain) Block in Th cell interaction with B cells B cells express IgD and IgM on membrane Increased IgM in serum Deficiency in IgG, IgA and IgE X-linked Recurrent infections e.g. IgA deficiency Due to defect in isotype switching Recurrent respiratory, gastrointestinal and/or genitourinary infection Hyper IgM Syndrome (HIgM) Pre B cells Mature B x-LA Proliferation Differentiation Isotype switching CVD IgA def. Plasma IgM HIgM Selective Ig class deficiency

Defects in Myeloid Lineage Progenitor Progenitor

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 granulocyte colony stimulating factor (G-CSF)

Defective Neutrophils Patients have neutrophils that are defective in NADP oxidase and production of reactive oxygen species (ROS) that is responsible for killing of phagocytosed microbes. This results in accumulation of granulocytes, Mf and T cells forming granulomas. These patients suffer from Chronic Granulomatous Disease. Have recurrent bacterial and fungal infections Commensals can become pathogenic X-linked or autosomal recessive Treated with antibiotics/IFN-g against infections

Overview of Primary Immunodeficiencies DiGeorge Syndrome (Autosomal dominant) SCID Common Variable Hypogglobulinemia/ X-linked hyperIgM Syndrome/Selective Ig deficiency Progenitor xLA Reticular Dysgenesis Progenitor Congenital Agranulocytosis Chronic Granulomatous Disease Auto rec./X-linked)

Secondary or Acquired Immunodeficiencies Agent-induced immunodeficiency: e.g. infections including HIV Metabolic disorders and trauma Splenectomy Drugs such as corticosteroids, cyclosporin A, radiation and chemotherapy Aging

Human Immunodeficiency Virus Discovered in 1983 by Luc Montagnier and Robert Gallo Is a member of genus retrovirus (RNA virus) belonging to Lentiviridae Characterized by long incubation period and slow course of disease HIV-1 (Common in US) and HIV-2 (in Africa) Patients with low CD4+ T cells Virus prevalent in homosexual, promiscuous heterosexual, i.v. drug users, transfusion, infants born to infected mothers Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium, etc. Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Course of AIDS Anti-HIV Ab/CTL ACUTE CHRONIC AIDS Dissemination of virus; Seeding of lymphoid organs Anti-HIV Ab/CTL ACUTE CHRONIC AIDS PHASE PHASE (<200cells/mm3)

Structure of HIV env (Envelope) (p24) (p17) Protease Matrix Capsid Integrase gag pol

Abs are ineffective to control HIV Virus grows intracellularly Abs develop after ~3 weeks. Thus cannot be used as a diagnostic test initially Reverse transcriptase is a sensitive test for diagnosis. Abs are not neutralizing

Role of T cells in development of AIDS Initially Th cells control viral load Cytopathic virus Syncitium formation with infected/uninfected cells Surviving Th cells are anergic Destruction of infected Th cells by CTL CTL that develop are ineffective because of high viral mutations Lack of Th cells affects CTL activation Resistance to CTL by downregulation of class I MHC on target cells

Coreceptors of HIV: In addition to gp120 binding to CD4, HIV has to bind coreceptors to gain entry into the cells. These coreceptors also serve as receptors for chemokines. Chemokine receptors T cell-tropic (Syncitium-inducing; X4 virus strain) Macrophage-tropic (Nonsyncitium-inducing; R5 virus strain) CD4 CXCR4: Ligand is SDF1 (Stromal cell derived factor) CD4 CCR5: Ligands are RANTES (Regulated on activation, normal T cell expressed and secreted), MIP1a, MIP1b (Macrophage Inflammatory Protein)