Immunodeficiency

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Immunodeficiency

• Mitzi Nagarkatti
• Professor and Chair,
• Dept. Pathology, Microbiology and Immunology
• Deputy Director, Basic and Translational Research
• SC Cancer Center
• USC School of Medicine
• Tel. [phone]
• E-mail mnagark_at_uscmed.sc.edu

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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

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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
• gt125 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

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Hematopoiesis
Progenitor
Progenitor
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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

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Allogeneic BM/HSC Transplantation
TCR
T cell
MHC
Thymus
MHC
Thymic Stromal Cells
MHC-matched for atleast1-2 alleles T cell
depleted
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Hematopoiesis
Progenitor
Progenitor
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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

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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

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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 Normal Mother Father Xx XY
Carrier x Carrier Mother Father Aa Aa
Normal x Affected Mother Father aa Aa
Autosomal Recessive Autosomal Dominant
X-linked
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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

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Hematopoiesis
Progenitor
Progenitor
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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.

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Types of SCID

• RAG-1/2 (Recombinase activating gene) deficiency
  Required for TCR and Ig gene rearrangement
• IL-2R gene defect
• 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

ADA
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DiGeorge syndrome
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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

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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
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Hyper IgM Syndrome
X-linked Agammaglobulinemia (x-LA)

• Absence of Igs and B cells
• Arrest at Pre-B cell stage (H-chain rearranged
  not L chain)
• Deficiency in IgG, IgA and IgE
• Increased IgM in serum
• B cells express IgD and IgM on membrane
• X-linked
• Recurrent infections
• e.g. IgA deficiency
• Due to defect in isotype switching
• Recurrent respiratory, gastrointestinal and/or
• genitourinary infection

Selective Ig class deficiency
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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

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Other Immunodeficiencies

• Bare lymphocyte syndrome
• Lack MHC class II on B cells, macrophages and
  dendritic cells
• Complement Deficiency

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Primary Immunodeficiencies
Stem Cell
Reticular Dysgenesis
Lymphoid Progenitor
Myeloid Progenitor
Severe combined Immunodeficiency SCID
Congenital Agranulocytosis
Pre-B
Monocyte
Pre-T
Neutrophil
x-linked agglobulinemia xLA
Mature B
Thymus
DiGeorge Syndrome d
Chronic Granulomatous Disease (x or r)
Mature T
Plasma Cell
Memory B
Common Variable Hypogglobulinemia / x-linked
hyperIgM syndrome/Selective Ig deficiency
Bare Lymphocyte Syndrome
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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

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Secondary or Acquired Immunodeficiencies

• Agent-induced immunodeficiency e.g. infections,
  metaboic disturbance, trauma, corticosteroids,
  cyclosporin A, radiation, chemotherapy
• HIV

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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

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Kaposi Sarcoma
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Incidence of HIV
CDC 2008
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Course of AIDS
Dissemination of virus Seeding of lymphoid
organs
Anti-HIV Ab/CTL
ACUTE CHRONIC AIDS PHASE PHASE
AIDS (lt200cells/mm3)
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Structure of HIV
env
(Envelope)
(p24)
(p17)
Protease
Matrix Capsid
Integrase
gag
pol
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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

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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

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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

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Viral Replication
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Coreceptors of HIV

• Chemokine receptors
• T cell-tropic (Syncitium-inducing X4 virus
  strain)
• 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)
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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

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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)

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Therapeutic targets
























Inhibit binding
Kuby, 2007
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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 )

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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

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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

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Reading

• Immunology
• By Male, Brostoff, Roth and Roitt
• 7th Edition
• Pages299-324