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Chapter 12 –Congenital and

AcquiredImmunodeficiencies

Dr. Hafez Sumairi

Learning outcomes

1.What are the mechanisms by which immunity iscompromised in the common immunodeficiencydiseases?

2.How does HIV cause the clinical and pathologicabnormalities of AIDS?

3.What approaches are being used to treatimmunodeficiency diseases?

• Immunodeficiency diseases are disorders caused by defectiveimmunity

• Congenital (or primary) immunodeficiencies are those result fromgenetic abnormalities in one or more components of the immunesystem

• acquired (or secondary) immunodeficiencies are those other defectsin the immune system may result from infections, nutritionalabnormalities, or medical treatments that cause loss or inadequatefunction of various components of theimmune system

Congenital (primary)immunodeficienciesCongenital immunodeficiencies are causedby genetic defects that lead to blocks in thematuration or functions of differentcomponents of the immune system

Defects in lymphocytematurationDisorders manifesting as defects in both theB cell and T cell arms of the adaptive immunesystem are classified as severe combinedimmunodeficiency (SCID)

Defects in lymphocytematurationX-linked SCID are caused by mutations in thecommon γ (γc) chain signalin subunit of thereceptors for several cytokines, includinginterleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, andIL-21.Autosomal SCID are caused by mutations inan enzymeAutosomal SCID are caused by mutations inthe RAG1 or RAG2 gene, which encode theVDJ recombinase that is required forimmunoglobulin (Ig) and T cell receptor generecombination and lymphocyte maturationDiGeorge syndrome is the most common. Itresults from incomplete development of thethymus (and parathyroid glands) and a failureof T cell maturation.

Defects in lymphocyteactivation and function• X-linked hyper-IgM syndrome is

characterized by defective B cell heavy-chainisotype (class) switching, so that IgM is themajor serum antibody, and by severedeficiency of cell-mediated immunityagainst intracellular microbes.

• The disease is caused by mutations in CD40ligand (CD40L), the helper T cell protein thatbinds to CD40 on B cells, dendritic cells, andmacrophages and thus mediates T cell–dependent activation of these cells

• Common variable immunodeficiency(CVID), these disorders are characterized bypoor antibody responses to infections andreduced serum levels of IgG, IgA, and oftenIgM.

• Bare lymphocyte syndrome is a diseasecaused by a failure to express class II MHCmolecules

Defects inlymphocyteactivation andfunction

Defects in innateimmunity

Acquired (secondary)immunodeficiencies

Acquiredimmunodeficiencysyndrome• Human immunodeficiency virus is a

retrovirus that infects cells of the immunesystem, mainly CD4+ T lymphocytes, andcauses progressive destruction of thesecells.

• The major cell types that may be infectedby HIV are CD4+ T lymphocytes,macrophages, and dendritic cells

Replication cycle of HIV1. Infection of cells

2. Production of viral DNA and

3. Its integration into the host genome,

4. Expression of viral genes, and

5. Production of viral particles

• Highly active antiretroviral therapy(HAART) or combination antiretroviraltherapy (ART)

Pathogenesis of AIDS• AIDS develops over many years as latent

HIV becomes activated and destroys cellsof the immune system

• The depletion of CD4+ T cells after HIVinfection is caused by a cytopathic effectof the virus, resulting from production ofviral particles in infected cells, as well asdeath of uninfected cells.

Clinical features of HIV infection and AIDS

Thank you