IMUNOLOGI "Immunodeficiency"

Objectives

— Definition

— Primary Immunodeficiencies

• —Characteristics
  —Types of primary immunodeficiency disorders
  —Mode of inheritance
  —Diagnosis and Treatment

—  Secondary Immunodeficiency

• —Human Immunodeficiency  Virus
  —Transmission
• —Therapy and prevention of AIDS

Immunodeficiency

Defect in 1 or more components of immune system

Types:

—  Primary or Congenital:

• —Born with the immunodeficiency
  —Inherited (Mutation in gene controlling immune cells)
  —Susceptible to recurrent, severe infection;  starting in children
  —Cannot recover without treatment
  —>125 immunodeficiency disorders

—  Secondary or Acquired: As a consequence of other diseases or environmental factors

                (e.g. infection, malignancy, aging, starvation, medication, drugs) – Human Immunodeficiency Virus

Hematopoiesis

Hematopoietic Stem Cell (HSC) deficiency 

• —HSC are multipotent (differentiate into all blood cell types)
  —Self renewing cells
  —Lineage negative (mature B/T cell, granulocyte, Mf markers absent)
  —CD34+, c-Kit+, Stem cell Ag (Sca-1+) on cell surface
  —Defect in HSC results in Reticular Dysgenesis
  —Affects development of all leukocytes
  —Patients are susceptible to all infections (bacterial, viral, parasitic and fungal)
  —Fatal without treatment
  —Treated with bone marrow or HSC transplantation

 

Allogeneic BM/HSC Transplantation

Hematopoiesi

Myeloid Progenitor Cell Differentiation Defect

• —Myeloid Progenitor Cells  develop into neutrophils and monocytes
  —Defect in differentiation from myeloid progenitor cells into neutrophils results in
    Congenital Agranulocytosis
  —Recurrent bacterial infections seen in patients
• —Treated with granulocyte-macrophage colony stimulating factor (GM-CSF) or G-CSF 

Defective Neutrophils

• Patients have neutrophils that are defective in production of reactive oxygen species that is 

responsible for killing of phagocytosed microrganisms. 

• —Nitroblue  tetrazolium test: reduction by superoxide (-ve)
• —This results in accumulation of granulocytes,  Mf and T cells forming granulomas.  These patients suffer from

                                Chronic Granulomatous Disease.

• Have recurrent bacterial infections
• Commensals become pathogenic
• —X-linked or autosomal recessive
• —Treated with IFN-g against infections

Inheritance

• 22 pairs of autosomes and 1 pair of sex chromosomes (X and Y)
• —Autosomal recessive (most AA normal; Aa carrier; aa affected)
• —Autosomal dominant (Aa affected; aa is normal)
• —X-linked (XX carrier daughter; XY affected son)

Carrier x Carrier
Mother    Father
   Aa          Aa

M	A	a
F
A	AA	Aa
	Normal	Carrier
a	Aa	aa
	Carrier	Affected

Autosomal Recessive


Normal x Affected
Mother     Father
aa              Aa

M	A	a
F
a	Aa	aa
	Affected	Normal
a	Aa	aa
	Affected	Normal

Autosomal Dominant


Normal x Affected
Mother     Father
Xx             XY

M	X	Y
F
X	XX	XY
	Normal	Normal
x	Xx	xY
	Carrier	Affected

X-linked 

Leukocyte Adhesion deficiency

• Adhesion molecule (e.g.CD18) may be lacking on T cells and monocytes.
• Autosomal recessive
• Results in defective extravasation
• Recurrent infections
• Impaired wound healing Treated with BM (depleted of T cells and HLA matched) transplantation or with gene therapy

Defect in Lymphoid Progenitor

• —Results in Severe Combined Immunodeficiency (SCID)
• —Lack T, B and/or NK cells
• —Thymus does not develop
• —Myeloid and erythroid cells are normal.
• —Generally lethal
• —Susceptible to bacterial, viral and fungal infections.
• —In infants, passively transferred maternal Abs are present.
• —Live attenuated vaccines (e.g. Sabin polio) can cause disease.

Types of SCID

—RAG-1/2 (Recombinase activating gene) deficiency: Required for TCR and Ig gene rearrangement

IL-2R gene defect  

                          ADA

Adenosine deaminase  (ADA) deficiency Adenosine-------->Inosine------>Uric acid T, B and NK cell 

deficiency due to toxicity of accumulated metabolites 

First successful gene therapy done in patient

DiGeorge syndrome

Precursor T cell differentiation defect

• Athymic  - DiGeorge Syndrome
• Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T regulatory (Treg) cells
• —B cells are present but T-dependent B cell responses are defective 
• —Anti-viral and anti-fungal immunity impaired 
• —Developmental defect in the 3rd and 4th pharyngeal pouch 
• Results  in facial defect and congenital heart disease 
• —Treated with thymic transplant
• Autosomal dominant trait

Nude Athymic mouse

 

nu/nu gene (autosomal recessive)

Hairless

Should be maintained in pathogen-free environment

T helper cell defect

Results in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defect

Accept xenografts

 

X-linked Agammaglobulinemia (x-LA)

—Absence of Igs and B cells

—Arrest at Pre-B cell stage (H-chain rearranged not L chain)

Hyper IgM Syndrome

—Deficiency in IgG, IgA and IgE

—Increased IgM in serum

—B cells express IgD and IgM on membrane

—X-linked

Selective Ig class deficiency

—e.g. IgA deficiency 

—Due to defect in isotype switching

—Recurrent respiratory, gastrointestinal and/or genitourinary infection

Common Variable Immunodeficiency

—B cells are normal

—Defect in maturation to plasma cells

—Decreased IgM, IgG and IgA or only IgG and IgA

—Susceptible to bacterial (e.g. pneumococci) infections

—Low Ab titers against DPT or MMR Vaccines

—Usually not detected in children because of maternal Abs

—Also called Late-onset hypogammaglobulinemia, Adult-onset agammaglobulinemia or Acquired agammaglobulinemia

—Ig replacement therapy and antibiotics

Other Immunodeficiencies

—Bare lymphocyte syndrome: 

Lack MHC class II on B cells, macrophages and dendritic cells

—Complement Deficiency

Primary Immunodeficiencies

Adaptive Immunity Deficiency

—T cell deficiency

—Susceptible to intracellular bacterial infection e.g. Salmonella typhi, Mycobacteria

— Susceptible to viral, parasitic and fungal infection

—B cell deficiency

—Susceptible to extracellular bacterial infection e.g. Staphylococcal infection

Secondary or Acquired Immunodeficiencies

—Agent-induced immunodeficiency: e.g. infections, metaboic disturbance, trauma, corticosteroids,

  cyclosporin A, radiation, chemotherapy

—HIV

Human Immunodeficiency Virus

—Discovered in 1983 by Luc Montagnier and Robert Gallo

—Retrovirus (RNA virus)

—HIV-1 (common) and HIV-2 (Africa)

—Patients with low CD4+ T cells

—Virus prevalent in homosexual, promiscuous heterosexual, i.v. drug users, transfusion, infants born to infected mothers

—Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium,  etc.

—Patients with HIV have high incidence of cancers such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

Course of AIDS

Structure of HIV

Abs are ineffective to control HIV

—Virus grows intracellularly

—Abs develop after ~3 weeks. 

—Thus cannot be used as a diagnostic test initially (Reverse transcriptase is a sensitive test)

—Abs are not neutralizing

Role of T cells in development of AIDS

—Initially Th cells control viral load

—Cytopathic virus

—Syncitium formation with infected/uninfected cells

—Surviving Th cells are anergic

—Destruction of infected Th cells by CTL

—CTL that develop are ineffective because of high viral mutations

—Lack of Th affects CTL activation

—Resistance to CTL by downregulation of class I MHC on target cells

Animal Models

—Primate Model:

—HIV grows in chimpanzees but do not develop AIDS

—Simian immunodeficiency virus (SIVagm in African green monkey – no disease; SIVmac in 

Macaques – AIDS like);

—Feline immunodeficiency  virus (FIV)

—Mouse Model:

—Grows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

Viral Replication

Coreceptors of HIV

—Chemokine receptors

—T cell-tropic (Syncitium-inducing; X4 virus strain)

CXCR4 : Ligand is SDF1 (Stromal cell derived factor)

—Macrophage-tropic (Nonsyncitium-inducing; R5 virus strain)

CCR5 : Ligands are RANTES (Regulated on activation, normal T cell expressed and secreted), MIP1a, MIP1b (Macrophage Inflammatory Protein);

Therapy

—Inhibit binding of gp120 with CD4 by

—Use of soluble CD4

—Use of anti-CD4 Abs

— Use of anti-gp120

—Inhibit binding of HIV to coreceptors by chemokines such as RANTES

Host Factors influencing course

—Transmission of HIV

—Sexual contact

—Breast feeding

—Transfusion

—During birth

—Sharing needles

—Resistance to HIV in individuals

—CCR5D32

—Some HLA types (HLA-A2) are resistant while others (HLA-B35) are susceptible)

Therapeutic targets

Treatment and Prevention

—Highly active anti-retroviral therapy (HAART; combination therapy) + IL-2 (to reconstitute the immune system)

—Vaccines: Proteins, DNA, subunit and recombinant virus (SIV-HIV chimeric virus)

Problems with therapy

—HIV-1 infection gives rise to AIDS despite the presence of Abs

—Low immunogenicity of virus

—Vaccine alone leads to destruction of CD4+ T cells

—Integration of virus in host genome

—Virus undergoes mutations

—High rate of virus replication (109 viruses/day)

—Live attenuated may result in AIDS

—Heat killed organism is not antigenic

—Vaccine administered through oral or respiratory route (Route of exposure to HIV is through genital tract)

—Lack of animal models and in vitro testing system

—Drugs do not cross blood-brain barrier to reach virus in brain

Summary

—Primary immunodeficiencies are inherited

—They can affect hematopoietic stem cells, lymphoid or myeloid cells.

—Secondary immunodeficiencies are due to infections, aging, cancer or chemical exposure

—HIV affects immune system by eliminating CD4+ T cells

—Vaccine development has been hindered by lack of an experimental model, antigenic variation, rapid proliferation of the virus

Reading

—Immunology

By Male, Brostoff, Roth and Roitt

7th Edition

Pages299-324