Immunodeficiencies S21 Notes PDF

4/7/21 The Immune System 1 Congenital and Acquired Immunodeficiencies Textbook chapter 12 2 1 4/7/21 Immunodeficiency Diseases Defects in the development and functions of the immune system result in increased susceptibility to newly acquired infections Disorders caused by defective immunity are call...

4/7/21 The Immune System 1 Congenital and Acquired Immunodeficiencies Textbook chapter 12 2 1 4/7/21 Immunodeficiency Diseases Defects in the development and functions of the immune system result in increased susceptibility to newly acquired infections Disorders caused by defective immunity are called immunodeficiency diseases Some of these diseases may result from genetic abnormalities in one or more components of the immune system; these are called congenital (or primary) immunodeficiencies Other defects in the immune system may result from infections, nutritional abnormalities, or medical treatments that cause loss or inadequate function of various components of the immune system; these are called acquired (or secondary) immunodeficiencies Acquired immunodeficiency syndrome (AIDS), which results from infection by human immunodeficiency virus (HIV) is one of the most devastating health problems worldwide 3 Immunodeficiency Diseases Congenital (primary) immunodeficiencies Acquired (secondary) immunodeficiencies 4 2 4/7/21 Congenital and Acquired Immunodeficiencies Congenital (primary) immunodeficiencies Acquired (secondary) immunodeficiencies 5 Congenital (Primary) Immunodeficiencies Congenital immunodeficiencies are caused by genetic defects that lead to blocks in the maturation or functions of different components of the immune system These immunodeficiencies share several features, the most common being infectious complications Some of these disorders result in greatly increased susceptibility to infections that may manifest early after birth and may be fatal unless the immunologic defects are corrected Other congenital immunedeficiencies lead to mild infections and may first be detected in adult life 6 3 4/7/21 Congenital (Primary) Immunodeficiency Defects in lymphocyte maturation Severe combined immunodeficiency (SCID) (B AND T Lymphocytes) Defects in RAG1 and RAG2 Defects in receptors specific for IL-2, IL-7 and IL-15 required for differentiation, proliferation and survival of lymphocytes (NK is also affected by IL-15) Defects in JAK3 which is involved in the signaling pathway of the above cytokines Defects in lymphocyte activation and function Defects in maturation of B OR T lymphocytes Defects in B and T cell response Defects in Burton Tyrosine Kinase (BTK) which is activated by the pre-B cell receptor (Xlinked agammaglobulinemia) Ig heavy chain deficiency Incomplete development of the thymus (DiGeorge syndrome) Defects in cytokines receptors such as IL-12, IFN-γ and IL-17 (Th1 and Th17 response) Mutations in CD40L results in Xlinked hyper IgM syndrome Defective MHCII expression (the bare lymphocyte syndrome) which affects T cell activation and T cell-mediated B cells activation (Defective maturation or activation?) 7 Sever Combined Immunodeficiency (SCID) X-SCID caused by γc mutations Mutations in γ chain (γc) signaling subunit of the receptors for several cytokines including IL2, IL-7 and IL-15 This results in reduced survival and maturation of lymphocyte precursors, deficient cell-mediated immunity, and defective humoral immunity NK cells are also affected because IL-15 is involved in NK cell proliferation and maturation Other mutations (JAK3, RAG1, RAG2) Rare cases of autosomal recessive SCID are caused by mutations in the RAG1 or RAG2 genes Mutation of the gene encoding JAK3 (involved in signaling by γc) result in the same abnormalities as those in X-linked SCID About half of the cases of SCID are X-linked, affecting only male children 8 4 4/7/21 X-Linked Agammaglobunemia (B Cells) No recombination Recombined H chain + μ Recombined H and L chain + μ Recombined H and L chain + μ + δ The disease is caused by mutations in the gene encoding Bruton tyrosine kinase (BTK) which is activated by the pre-B cell receptor expressed in pre-B cells, and it delivers signals that promote the survival, proliferation, and maturation of these cells 9 Ig Heavy Chain Deficiencies Heavy chain The result of chromosomal deletion involving Ig heavy chain locus Deficiency in IgG, IgA and IgE 10 5 4/7/21 Defects in Maturation of T Lymphocytes DiGeorge syndrome (T Cells): Selective defects in T cell maturation are quite rare. Of these, DiGeorge syndrome is the most frequent which results from incomplete development of the thymus Patients with DiGeorge syndrome fail to develop mature T cells The condition tends to improve with age, probably because the small amount of thymic tissue that does develop is able to support some T cell maturation 11 Therapy of Congenital Immunodeficiencies SCID is fatal in early life unless the patient’s immune system is reconstituted. The most widely used treatment is hematopoietic stem cell transplantation, with careful matching of donor and recipient For selective B cell defects, patients may be given intravenous injections of pooled immunoglobulin (IVIG) from healthy donors to provide passive immunity In all patients with these diseases, infections are treated with antibiotics as needed 12 6 4/7/21 The Bubble Boy (SCID) David Vetter (1971-1984) suffered from SCID and lived in a sterile hospital room for all of his life 13 Congenital and Acquired Immunodeficiencies Congenital (Primary) Immunodeficiencies Acquired (Secondary) Immunodeficiencies 14 7 4/7/21 Acquired (Secondary) Immunodeficiencies Deficiencies of the immune system often develop because of abnormalities that are not genetic but are acquired during life The most serious of these abnormalities worldwide is HIV infection 15 Acquired (Secondary) Immunodeficiencies 16 8 4/7/21 Acquired Immunodeficiency Syndrome (AIDS) Acquired immunodeficiency syndrome (AIDS) was first recognized as a distinct entity in the 1980s AIDS is caused by infection with HIV which leads to 1 to 2 million deaths annually Effective antiretroviral drugs have been developed, but the infection continues to spread in parts of the world where these therapies are not widely available, and in some African countries, more than 30% of the population has HIV infection 17 How do Viruses Copy their Genomes? (RNA Viruses - Using Reverse Transcriptase Enzyme) ssRNA viruses use reverse transcriptase enzyme to generate dsDNA which can integrate with the host chromosome cDNA Double-stranded cDNA cDNA template RNA template First, reverse transcriptase synthesizes cDNA from RNA Then, reverse transcriptase synthesizes double-stranded DNA from cDNA Retrovirus © 2017 Pearson Education, Inc. 18 9 4/7/21 Human Immunodeficiency Virus (HIV) An infectious HIV particle consists of two RNA strands within a protein core, surrounded by a lipid envelope derived from infected host cells but containing viral proteins The viral RNA encodes structural proteins, various enzymes, and proteins that regulate transcription of viral genes and the viral life cycle HIV is a retrovirus that infects cells of the immune system, mainly CD4+ T lymphocytes, and causes progressive destruction of these cells 19 Human Immunodeficiency Virus (HIV) CXCR4 and CCR5 20 10 4/7/21 The Life Cycle of HIV The integrated viral DNA is called a provirus 21 The Life Cycle of HIV infection of cells, production of a DNA copy of viral RNA and its integration into the host genome, expression of viral genes, and production of viral particles Envelope glycoprotein, gp120 (for 120-kD glycoprotein) binds to CD4 and to CXCR4 and CCR5 (chemokine receptors) on CD4+ T lymphocytes (can also infect macrophages and DC) The viral membrane fuses with the host cell membrane, and viral RNA released into the cytoplasm of the host cell A DNA copy of the viral RNA is synthesized by the viral reverse transcriptase enzyme (a process characteristic of all retroviruses) DNA integrates into the host cell’s DNA by the action of the integrase enzyme. The integrated viral DNA is called a provirus 22 11 4/7/21 The Life Cycle of HIV If the infected T cell, macrophage, or dendritic cell is activated by another infectious microbe, the cell responds by turning on the transcription of many of its own genes and often by producing cytokines A negative consequence of this normal protective response is the activation of the provirus, leading to production of viral RNAs and then proteins The integrated HIV provirus may remain latent within infected cells for months or years, hidden from the patient’s immune system 23 Pathogenesis of HIV HIV infects CD4+ T cells, dendritic cells, and macrophages at sites of entry through epithelia; in lymphoid organs such as lymph nodes; and in the circulation In mucosal tissues at the sites of entry, there may be considerable destruction of infected T cells which has a significant functional deficit as a large fraction of the body’s lymphocytes, and especially memory T cells, reside in these tissues Dendritic cells may capture the virus as it enters through mucosal epithelia and transport it to peripheral lymphoid organs, where it infects T cells The integrated provirus may be activated in infected cells, leading to production of viral particles and spread of the infection 24 12 4/7/21 Pathogenesis of HIV The mechanism of this T cell loss remains poorly defined. One possibility is that T cells are chronically activated, perhaps by infections that are common in these patients, and the chronic stimulation culminates in apoptosis Other infected cells, such as dendritic cells and macrophages, may also die, resulting in destruction of the architecture of lymphoid organs Loss of T cells (followed by fall in the blood CD4+ T cell count) is the most reliable indicator of disease progression 25 Pathogenesis of HIV In the lymph node, the virus infects CD4+ T cells regardless of their TCR specificity DCs displaying HIV peptides on both MHCI and MHCII cross present the HIV peptides (to CD8+ and CD4+ T cells) which have TCRs specific for HIV HIV specific CTL and antibodies partially control viral replication If resting CD4+ T cells which are infected with HIV virus, get activated by their specific antigens, the latent provirus will start replication Figure, Text book page 262 26 13 4/7/21 Therapy and Vaccination Strategies The current treatment for AIDS is aimed at controlling replication of HIV and the infectious complications of the disease Combinations of drugs that block the activity of the viral reverse transcriptase, protease, and integrase enzymes are now being administered early in the course of the infection This therapeutic approach is called highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (ART) The virus is capable of mutating its genes, which may render it resistant to the drugs used, and reservoirs of latent virus are not eradicated by these drugs 27 Drug Targets for HIV Why is it difficult to develop antiviral drugs? Because they do not have their own metabolic activities to target Because they can mutate their genes 28 14 4/7/21 Drug Targets for HIV HIV has four proteins/enzymes that could be targeted: 1. gp120 viral binding protein 2. Reverse transcriptase enzyme 3. Integrase enzyme 4. Protease enzyme 29 15