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.