Immunodeficiency Disorders & Neoplasias Lecture Notes PDF

Learning Objectives Compare and contrast primary and secondary 1. immunodeficiencies. Describe selected immunodeficiency conditions that 2. occur. Indicate the main clinical features of selected 3. immunodeficiency disorders and the immune mechanisms that lead to tho...

Learning Objectives Compare and contrast primary and secondary 1. immunodeficiencies. Describe selected immunodeficiency conditions that 2. occur. Indicate the main clinical features of selected 3. immunodeficiency disorders and the immune mechanisms that lead to those clinical features. Describe treatment and therapeutic options for 4. selected immunodeficiency disorders. Describe selected cancers associated with deficiencies 5. in the immune system.  Immune System Disorders Disorders of the immune system can be characterized by o absences – immunodeficiencies o excesses (uncontrolled proliferations) – neoplasias o loss of tolerance (lecture 21) o autoimmune disease (lecture 23) 2 Immunodeficiencies 3  Immunodeficiencies Hallmark of these disorders is the enhanced susceptibility to infections o frequent/chronic illness by infectious organisms o common illness that lasts longer/is more severe than normal o disease due to opportunistic or commensal organisms o disease that fails to respond normally to treatment ▪ e.g. abx may need to be taken longer 4  Immunodeficiencies Other health issues can include o anemia o arthritides/joint pain o ~25% also have an autoimmune disease o neoplasias (leukemias or lymphomas) o growth retardation 5  Immunodeficiencies There are two categories o congenital: AKA – primary (PI) ▪ disease stemming from a genetic defect o acquired: AKA – secondary ▪ develops as a consequence of another disease or condition As many as 1 in 500 people have a PI o due to the redundancies of the immune system, only about 1 in 10,000 experience significant disease associated with the PI 6 1o Immunodeficiencies 7  1o Immunodeficiencies Likely to manifest in childhood Can be divided into the type of immune function (e.g. humoral, complement) SCID (severe combined immunodeficiency) is a family of disorders that affect more than one part of the immune system o always involves T cells, but may also include B cells, or NK cells o the defect may be in T cells, but can affect B cell function due to their dependence on T cell “help” 8  1o Immunodeficiencies Most common types of 1o immunodeficiencies 9 There are 430 known primary immunodeficiencies Gene(s) has been identified for 343 of them 9  Cellular PIs Hemophagocytic Lymphohistiocytosis (HLH) o there are primary (genetic) & secondary forms (infectious agent-induced, cancers, immunodeficiency disorders, drug-induced) o most common in patients birth – 18 mos (but seen in children & adults) o what does HLH mean? hemophagocytic lymphohistiocytosis blood phagocytic relating to an excess of cells the macrophages lymphatic system 10  Cellular PIs Hemophagocytic Lymphohistiocytosis (HLH) o cause: ▪ mutations in genes involved in perforin- granzyme killing by CTLs & NK cells e.g. mutation in the perforin gene prevents the synthesis of perforin e.g. mutation in the gene that prevents the vesicle containing perforin & granzyme from fusing with the outer membrane for release o CTLs & NK cells respond to intracellular pathogens by secreting IFN-γ to activate mΦs ▪ the lack of killing leads to continued production of IFN-γ causing over activation of mΦs 11  Cellular PIs Hemophagocytic Lymphohistiocytosis o symptoms/clinical manifestations: ▪ excessive inflammation severe systemic inflammatory syndrome that can be fatal ▪ increase in viral & intracellular infections ▪ phagocytosis of RBCs → anemia → fatigue ▪ low levels of platelets, neutrophils, hemoglobin ▪ splenomegaly In this example the defect is in the T cell or NK cell, but the response is in macrophage overactivation & opsonization 12  Cellular PIs Hemophagocytic Lymphohistiocytosis o treatment: ▪ methotrexate & prednisone (neurological implications) ▪ anti-IFN-γ ▪ etoposide ▪ dexamethasone ▪ cyclosporine A ▪ bone marrow transplant 13  Humoral PIs Selective IgA Deficiency o AKA: dysgammaglobulinemia o most common of all PIs o cause: ▪ defect in B cell development into IgA- secreting plasma cells ▪ IgA genes are normal – the defect is in the differentiation process after clonal proliferation Selective Ig immunodeficiencies have been associated with all the isotypes 14  Humoral PIs Selective IgA Deficiency o symptoms/clinical manifestations: ▪ recurrent infections, particularly in mucosal tissues (GI, respiratory) ▪ more prone to allergies, asthma, RA, diabetes ▪ low levels of IgA, but normal levels of IgM & IgG ▪ normal numbers of peripheral B cells o treatment: Why not just provide IgA? ▪ antibiotics as needed for infections 15  Humoral PIs Activation-Induced (Cytidine) Deaminase (AID) Hyper IgM Syndrome 2 o cause: ▪ mutation in the AID enzyme AID induces class switch recombination (isotype switching) in B cells within the follicles the expression of this enzyme is induced upon CD40-CD40L interaction with the TH cell o there are several forms & causes of HIGM syndrome but HIGM 2 is the most common 16  Humoral PIs Activation-Induced (Cytidine) Deaminase (AID) Hyper IgM Syndrome 2 o symptoms/clinical manifestations: ▪ # of peripheral CD19+ B cells is normal ▪ lack of switched isotypes ▪ IgM levels may be elevated, but are often within normal range ▪ patients often develop hemolytic anemia o treatment: ▪ IVIg ▪ antibiotics as needed for infection 17  Humoral PIs Other causes of Hyper IgM Syndrome o HIGM 1 (X-linked) ▪ CD40L mutations (T cell defect) ▪ because the defect is in T cells, it is a SCID o HIGM 3 ▪ CD40 mutations (B cell defect) o HIGM 4 ▪ breaks occur in the switch region upstream of the Cµ gene (B cell defect) o HIGM 5 ▪ Uracil DNA Glycosylase (UNG) (B cell defect) 18  Humoral PIs NL: normal levels Bonilla, F. A., et. al. ICON: Common Variable Immunodeficiency Disorders. JACI Pract. 2015 In pts with hyper-IgM, the level of IgM may be high or within normal range, but the ratio of IgM to IgG is higher than normal. There should be ~ 12 mg/dL of IgG and ~ 1.8 mg/dL of IgM, but this may be skewed more toward IgM if isotype switching is decreased/impaired. 19  SCID Bare Lymphocyte Syndrome o lack of MHC class I (BLS Type I) or class II molecules (BLS Type II – more common) o cause: ▪ defect in class I expression is due to mutation in tap1 or tap2 gene (i.e. MHC class I molecules are made, but not displayed on the cell surface) ▪ defect in class II expression is due to mutations in transcription factor (i.e. MHC class II molecules are not made) ▪ in both cases the MHC genes are normal 20  SCID Bare Lymphocyte Syndrome Class I Defect Class II Defect mutation in tap genes mutation in Tx factor 21 Immunology, Infection, and Immunity , 2004  SCID Bare Lymphocyte Syndrome o lack of circulating CD4+ or CD8+ αβ thymocytes due to lack of MHC molecules for positive selection during thymocyte development o there is a normal number of mature γδ T lymphocytes o studies have shown that NK cells developing in a MHC class-I-negative environment become tolerant to MHC class-I-deficient cells 22  SCID Bare Lymphocyte Syndrome I o symptoms/clinical manifestations: ▪ necrotizing granulomatous skin lesions ▪ respiratory bacterial infections – H. influenzae, S. pneumoniae, S. aureus, K. pneumoniae, E. coli, & P. aeruginosa ▪ they don’t have an increase in viral infections ▪ most patients reach adulthood with proper treatment of infections 23  SCID Bare Lymphocyte Syndrome I o treatment options: ▪ lung transplant (since the most severe & common infections are respiratory, lung damage is a common outcome) ▪ antibiotics as needed for infections o other protective measures: ▪ vaccines, especially for respiratory pathogens 24  SCID Bare Lymphocyte Syndrome II o more common in those of Mediterranean or N. African descent o symptoms/clinical manifestations: ▪ repeated & persistent infections by bacterial, viral, fungal, & opportunistic pathogens ▪ because of frequent/persistent GI infections, infants experience difficulty absorbing nutrients → failure to thrive o treatment: ▪ fatal by adolescence unless treated with HSCT 25  Phagocytic PIs Chronic Granulomatous Disease AKA: Bridges–Good syndrome o cause: ▪ dysfunction in one of the enzymes involved in the oxidative (See lecture burst (such as NADPH oxidase) 4 slide 10) used to kill phagocytosed pathogens in the phagolysosome ▪ results in pathogens surviving inside of mΦs & neutrophils once phagocytosed ▪ phagocytic cells fuse together forming granulomas Abbas: Basic Immunology: Functions and Disorders of 26 the Immune System , 2016  Phagocytic PIs Chronic Granulomatous Disease o symptoms/clinical manifestations: ▪ increased susceptibility to opportunistic pathogens (mostly bacteria & fungi) ▪ more frequent/serious soft tissue infections ▪ oral/gum disease ▪ chronic respiratory & urologic disorders ▪ abscess formation (brain, liver, lungs, bone) o treatment: ▪ prophylactic antibiotics or antifungals 27  Phagocytic PIs Leukocyte Adhesion Deficiency (LAD) o LAD-1: mutation in one of the genes encoding CD18 – an integrin required for extravasation ▪ CD18 is a heterodimer, so 1 chain of this integrin is not expressed normally o LAD-2: mutation in sialyl-Lewis X in neutrophils & leukocytes resulting in a loss of migration for these cells o LAD-3: mutation in the signaling pathway for upregulation of selectins on leukocytes 28  Phagocytic PIs Leukocyte Adhesion Deficiency (LAD) 1 o cause: ▪ mutation in a component of CD18 o symptoms/clinical manifestations: ▪ loss of neutrophil migration → neutrophilia ▪ recurrent soft tissue infections – including the gums → loss of teeth ▪ lack of pus formation ▪ poor wound healing ▪ delayed umbilical cord separation o LAD-I patients usually die before 1 yoa 29  Phagocytic PIs Leukocyte Adhesion Deficiency (LAD) 2 o cause: ▪ impaired fucose metabolism resulting in an absence of sialyl-Lewis X on leukocytes & neutrophils ▪ a ligand for vascular endothelial selectins → leukocytes cannot bind selectins for extravasation o clinical manifestations ▪ loss of neutrophil migration → neutrophilia ▪ increased incidence of infection ▪ neurological & severe developmental & physical/growth abnormalities 30  Phagocytic PIs Leukocyte Adhesion Deficiency (LAD) 3 o LAD-3 presents clinically like LAD-1 (See lecture 3 ▪ due to a lack of selectin expression & poor slides 36, 37) leukocyte migration into the tissues o cause: ▪ defective signaling required for upregulation of adhesins on the leukocytes o symptoms/clinical manifestations ▪ defective platelet aggregation (platelet counts are normal) → life-threatening bleeding disorder ▪ delayed umbilical cord separation 31  Complement PIs C1, C2, or C4 deficiencies o little to no increase in infections o associated with immune complex formation ▪ RA, SLE, vasculitis C5-C9 MAC deficiencies ▪ more frequent, recurrent & invasive infections by Neisseria species (meningitidis & gonorroheae) C3 deficiency (most severe) ▪ Increased susceptibility to encapsulated bacterial pathogens 32  Complement PIs Complement regulatory proteins o abnormal activation of complement o C1INH deficiency ▪ uncontrolled activation of C4 & C2 results in the release of large of amounts of vasoactive peptides (C2 kinin) leading to edema & a condition known as hereditary angioedema 33 2o Immunodeficiencies 34  2o Immunodeficiencies Patients are born with a healthy immune system Deficiency results from a contributing factor or occurrence that causes a decreased immune response o can be due to the factors associated with the state of health of the patient ▪ age, stress, alcoholism, smoking, lack of sleep o can be due to biological causes ▪virus, diabetes, cancer o many therapies decrease immunity ▪ mAb, small molecule inhibitors (__nib drugs) 35  2o Immunodeficiencies Most common non-biological cause is malnutrition Best known biological cause is AIDS resulting from HIV infection Much more common than PIs 36 Neoplasias 37 Neoplasms of the Immune System Cancers involving the immune system can be classified as leukemias or lymphomas o leukemias – proliferate as individual cells (lymphoid or myeloid) o lymphomas – proliferate as a mass of cells 38 39 Neoplasms of the Immune System ALL – Acute Lymphocytic/blastic Leukemia o dysregulated proliferation & clonal expansion of a lymphoid progenitor cell (usually a B cell) o most common malignancy dxd in children – represents about 1/3rd of all pediatric cancers o found in children & adults o anemia (fatigue), pale skin, headaches, enlarged lymph nodes/liver/spleen, excessive/unexplained bruising or bleeding 40 Neoplasms of the Immune System CLL – Chronic Lymphocytic/blastic Leukemia o usually involves mature circulating B cells which cannot undergo apoptosis due to a genetic alteration o accounts for ~ 1/3rd of all leukemias o healthy B cells are not made → lower antibody response → increase in infections o occurs mostly in adults (55+) 41 Neoplasms of the Immune System AML – Acute Myeloid (Myelogenous or Myelocytic) Leukemia o malignant proliferation of immature granulocyte precursor cells o malignant cells crowd out the development of normal cells in the bone marrow ▪ leads to low WBC numbers & ↑ infections o eventually leads to a lack of RBCs & platelets → anemia & bleeding o found in children & adults 42 Neoplasms of the Immune System CML – Chronic Myeloid (Myelogenous or Myelocytic) disorders o Granulocytes – Chronic Myelocytic Leukemia o Megakaryocytes – Malignant thrombocytopenia o Megakaryocytes – Myeloid metaplasia o RBCs – Polycythemia vera o All are more common in adults 43  Neoplasms of the Immune System Multiple Myeloma (Plasmacytoma) o malignant B cells that have differentiated into plasma cells o accumulate as a mass in bone o bone is destroyed, creating “punched out” holes – especially in the spine & skull (these holes are diagnostic) o normal B cells cannot be made 44 Neoplasms of the Immune System Multiple Myeloma (Plasmacytoma) o occurs mostly in older adults o more common in those of African American & native Pacific Islanders descent o most develop renal failure due to Bence- Jones proteins (overproduction of L chains) which pass through the kidney 45 orthoinfo.aaos.org medscape.com Neoplasms of the Immune System Hodgkin vs. Non-Hodgkin Lymphoma o these are the two broad categories of lymphomas Hodgkin lymphoma is more common in patients 15-24 yoa o ~8,000 cases/year in the US Non-Hodgkin lymphoma is more common in patients 60+ o ~70,000 cases/year in the US 46  Neoplasms of the Immune System Hodgkin Lymphoma o spread from lymph node to lymph node in an orderly & predictable fashion o have a histological finding of Reed-Sternberg cells ▪ Reed-Sternberg cells are a lymphoblastic form of a mature B cell 47 Neoplasms of the Immune System Hodgkin Lymphoma o often begin in neck region (cervical LNs) o malignant RS cells may arise from a previous EBV infection o most prevalent in teens & young adults o predictable nature makes it quite treatable with ~90% surviving beyond 5 years 48 Neoplasms of the Immune System Non-Hodgkin Lymphoma o B cell or T cell malignancies o more aggressive & less predictable – may arise in abdomen or groin o spreads beyond the lymph nodes (spleen, liver, bone marrow) o usually more advanced when dx is made o advanced stage at dx & unpredictable pattern of spread reduce prognosis ▪ ~74% survive beyond 5 years (lower if dxd at stage 3 or 4) 49