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MICR 304 Immunology &
Serology
MICR 304 Immunology &
Serology
Lecture 16Immunodeficiency Diseases
Chapter 12.7-
Lecture 16Immunodeficiency 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
ComplementC1 Inhibitor deficiency, C5-9 deficiency
PhagocytesChronic granulomatous diseaseLeukocyte adhesion deficiency
Antibodies (B-cells)X-linked ammaglobulinemia
X-linked hyper IgM syndromeT- cells
X-linked c SCIDB+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 inChronic Granulomatous
Disease
Nitro blue tetrazolium is reduced by NADPH oxidase to yield an insoluble
blue formazan salt.
Normal
Patient
Carrier
Altered NBT Test
Aspergillus pneumonia in CGD
patient
Pneumonia
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
Sele
cted s
yndro
mes
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
Cytokine Major EffectsIL2 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-, 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
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.