MICR 304 Immunology & Serology Lecture 16 Immunodeficiency Diseases Chapter 12.7-

Overview of Today’s Lecture Inherited immunodeficiencies Immunoglobulins Complement Phagocytes T cells Acquired immunodeficiencies Artificial AIDS

Immunodeficiencies Caused by defects of one or more components of the immune system Recurrent infections Often opportunistic microbes

Susceptibility for Infections Defects in complement, phagocytes, antibodies: Extracellular bacteria, pyogenic infections Defects in T-cells: Fungal and viral infections, infections with intracellular pathogens

Compare and Contrast Inherited and Acquired Immune Deficiencies Inherited defects of the immune system Alterations in genes involved in immunity Symptomatic from infancy on Acquired defects of the immune system Various causes Typically develop later

Our most Important Defense Weapons Complement: to opsonize, initiate inflammatory response, and to kill Antimicrobial peptides: to kill and to modulate immune response Phagocytes: to remove microbes, prevent further spread, to kill and in some cases to initiate adaptive immune response Antibodies: to neutralize, opsonize, and to agglutinate Granuloma formation: a concerted action to wall off and ultimately kill intracellular microbes NK cells and CTLs: to remove infected (or maligne) host cells via apoptosis and indirectly kill microbial invaders TH and regulatory T cells: to orchestrate the immune response

Evaluation of the Immune System

Inherited Immune Defects Discussed Today Complement C1 Inhibitor deficiency, C5-9 deficiency Phagocytes Chronic granulomatous disease Leukocyte adhesion deficiency Antibodies (B-cells) X-linked ammaglobulinemia X-linked hyper IgM syndrome T- cells X-linked gc SCID B+T cells ADA deficiency

Complement System C1INH DAF Proctectin Factor I

Complement Deficiencies Lack of active complement factors: C3 damage: wide range of pyogenic infections (S. aureus, S. pyogenes etc) Overall and in particular with C5-9 deficiency increased Neisseria infections 10,000 x risk increase Lack of control proteins C1 Inhibitor: angioneurotic edema Decay accelerating factor: spontaneous hemolytic attacks Factor I: consumption of complement, lack of complement

Phagocyte Defects Chronic Granulomatous Disease NADPH oxidase defect Many different gene mutations No superoxide radical production Host forms granulomas to eliminate pathogens Leukocyte adhesion deficiency Mutations in sialyl lewis (ligand for selectin) or intergrins Prevents leukocyte migration to the locus of infection

Diagnostics in Chronic Granulomatous Disease Aspergillus pneumonia in CGD patient Pneumonia Altered NBT Test Normal Patient Carrier Nitro blue tetrazolium is reduced by NADPH oxidase to yield an insoluble blue formazan salt.

X-Linked Agammaglobulinemia (XLA) Failure to produce antibodies Increase in infections with pyogenic bacteria e.g. S. pyogenes and chronic viral infections e.g. hepatitis B Mutations in X-chromosome One of the common: Bruton’s Disease Mutation in Bruton’s tyrosine kinase (Btk) Signal transduction defect in pre-B cells No stimulation in response to Ag Arrest of B-cell development B-cells rarely found in peripheral blood

Consequences of Btk Mutation In normal males, only X-chromosome is active In affected male no B-cell development In female carriers, only B-cells that have randomly inactivated the defect chromosome mature All mature B-cells have the nondefective x-chromosome activated Non-random X chromosome inactivation only in B cells Signal transduced via Btk

Onset of XLA When maternal antibodies fade

Absence of Immunoglobulins in Serum from XLA Patients

Absence of B-Cells in XLA Flow cytometer analysis CD19: B-cell marker CD3: T-cell marker

Refresher: B-Cell Activation by T-Cells

Hyper IgM Syndrome Normal B and T cell development but lack of IgG, IgA, and IgE B-cell activation by T-cells is disrupted CD40 ligand deficiency in T-cells prevents activation of otherwise normal B-cells X-linked Also defective in cell mediated immunity Mutations in CD40 in B cells Mutation of NFkB pathways in B-cells (NEMO) AID deficiency No isotype switch after antigen recognition Lymphoid tissues are devoid of germinal centers Selected syndromes

AID Deficiency Mutation in gene for activation induced cytidine deaminase Subform of hyper IgM syndrome Defective B cells with lack of isotype switch More susceptible to severe bacterial infections but not to opportunistic infections e.g. P. carinii pneumonia

Severe Combined Immunodeficiencies B and T cell function is affected Causes can be primary T cell defects or T and B cell defects Without T cells lack of T cell dependent antibodies Cell mediated immune responses Immunological memory Severe opportunistic infections Adenoviruses EBV Candida albicans P. carinii

Major Causes of SCID

X-Linked SCID with Common Gamma Chain Mutation Common gamma chain of the following cytokine receptors affected: IL2, IL4, IL7, IL9, IL15, IL21 Predominantly T-cell defect No T-cell development, no NK cells B cell numbers are normal but not their function Lack of macrophage activation and B-cell activation X-linked

Refresher: Selected Cytokines Major Effects IL2 T cell proliferation IL4 B cell activation, IgE switch, TH2 differentiation IL7 Growth of pre-B cells and pre-T cells IL9 Mast cell enhancing activity, TH2 stimulation IL15 Stimulates growth of T cells, NK cells, enhances CD8 memory T cell survival IL21 Induces proliferation of B, T, and NK cells

Autosomal SCID: ADA Deficiency Adenosine deaminase deficiency Alterations in purine degradation Accumulation of nucleotide metabolites In particular toxic for T-cells, also B-cells General lack of T and B-cell function

Refresher: T-Cells and Granuloma Formation Functional T cells are essential in clearing infections with intracellular pathogens.

Acquired Immune Deficiencies Natural: newborns Immune suppressive therapy Cyclosporin (transplantation) Steroids (autoimmune diseases, chronic inflammation) Tumor patients Neutropenia during therapy Cytokine production (TGF-b, IL10) Chronic Disease Infections Measles HIV and AIDS

Transient Immunoglobulin Deficiency in Newborns

HIV Infection is Pandemic

HIV Virus Retrovirus Infects CD4+ cells: TH cells, dendritic cells, macrophages, monocytes Requires co-receptor: chemokine receptor Tropism depends on chemokine receptor CCR5: DC, MP, CD4 T Ly R5 virus Mutations protect against HIV infection CXCR4: activated T Ly X4 virus

Dendritic Cells Transport HIV to Lymphnodes

Typical Course of Untreated HIV Infection

Immune Response to HIV

HIV Associated Diseases T- cell defect Lack of macrophage activation Intracellular opportunistic infections Lack of effective CTLs Development of virus- associated tumors

Tumors Associated with HIV Infection Remember T-helper cells activate NK cells New Herpes viridae are involved that are not eliminated Lymphoma, Kaposi sarkoma

Diagnostics of Immune Deficiencies Complement: CH50 test Phagocytes: NBT test, phagocytosis and killing tests Antibodies: immune electrophoresis B-cells: pokeweed stimulation, induced antibody response T cells: unspecific lymphocyte stimulation with phytohemagglutin, skin tests

Therapeutic Approaches for Immune Deficiencies Symptomatic Ig treatment Bone marrow transplantation Gene therapy Remove bone marrow Insert new gene into collected cells Re-implant bone marrow Antiviral therapy

Bone Marrow Grafting is Problematic Can be prevented by T-cell depletion of donor marrow

Often requires up to 40 pills a day. HIV Therapy Reverse Transcriptase Inhibitors Protease Inhibitors Virus decoys (material to which virus binds instead of to cells) Boosting immune system Often requires up to 40 pills a day.