Pharmacy-Immunology 19

Primary & Acquired Immunodeficiency

Saber Hussein

Objectives

• Know the types of primary (congenital) immunodeficiency that result of:

– Defects in B and T lymphocytes maturation

– Defects in lymphocytes activation and function

– Defects in innate immunity

– Lymphocyte abnormalities associated with other diseases

• Know the acquired (secondary) immunodeficiency syndrome (AIDS) in regard of:

– Structure and biology of HIV

– Clinical features of HIV infection and pathogenesis of AIDS

– AIDS therapeutic and vaccination strategies

Features of immunodeficiency diseases• Diagnostic features and clinical manifestations of immune

deficiencies affecting components of the immune system• Different diseases, and even different patients with the same

disease, may show considerable variation

Fig12-1

(Extracellular bacterial infections)

Congenital immunodeficiencies

• Primary Immunodeficiencies are congenital diseases caused by genetic defects that inhibit maturation of B or T cells or interfere with functions of immune components

• Prevalence: 1 in 500 American and European

• Hallmark of immunodeficiencies’ consequences:– Infections that could be mild or severe, start in early

childhood or in adulthood

Congenital immunodeficiencies caused by defects in lymphocyte maturation

• Autosomal SCID (severe combined immunodeficiency) caused by:

– ADA (adenosine deaminase) & PNP (purine nucleoside phosphorylase) deficiency prevent maturation of:

• Stem cell pro-B cell

• Pro-B cell pre-B cell

• Stem cell pro-T cell

• Pro-T cell pre-T cell

– RAG (recombination activating gene) deficiency prevents maturation of:

• Pro-B cell pre-B cell

• Pro-T cell pre-T cell

• X-linked SCID:– Signaling IL-2Rg chain (c is common in IL receptors of IL-2,

IL-4, IL-7, IL-9, IL-15) deficiency interferes with• Pro-T cell pre-T cell [see Fig12-2, next slide]

Fig12-2:Congenital

immunodeficiencies

Fig12-2:Congenital immunodeficiencies

Features of congenital immunodeficiencies caused by defects in lymphocyte maturation

Fig12-3

Features of congenital immunodeficiencies caused by defects in lymphocyte maturation

Fig12-3

Congenital immune-

deficiencies associated

with defects in

lymphocyte activation

and effector functions

• Congenital immunodeficiencies may be caused by genetic defects in the expression of molecules required for – Ag presentation to T cells,

– T or B lymphocyte antigen receptor signaling,

– helper T cell activation of B cells and macrophages, and

– differentiation of antibody-producing B cells.

Fig12-4 :Sites where immune responses may be blocked

Congenital immunodeficiencies associated with defects in lymphocyte activation and effector functions

Fig12-4: Features of some of resulting deficiency disorders

Congenital immunodeficiencies caused by defects in innate immunity

Fig 12-5

Congenital immunodeficiencies caused by defects in innate immunity

Fig 12-5

Acquired (secondary) immunodeficiency diseases

Fig 12-6

HIV life cycleFig 12-8

HIV life cycle

The pathogenesis of HIV-AIDS

• The stages of HIV disease correlate with a progressive spread of HIV from the initial site of infection to lymphoid tissues throughout the body.

• The immune response of the host temporarily controls acute infection but does not prevent establishment of chronic infection of cells in lymphoid tissues.

12-9

The pathogenesis of HIV-AIDS

• The host’s immune response temporarily controls acute infection

• But establishment of chronic infection of cells in lymphoid tissues succeeds

• Cytokines produced in response to HIV and other microbes serve to enhance HIV production and progression to AIDS

12-9

The clinical course of HIV disease• Blood-borne HIV virus (plasma viremia) is detected

early after infection • It may be accompanied by systemic symptoms typical of

acute HIV syndrome• The virus spreads to lymphoid organs, but• plasma viremia falls to very low levels (only detectable

by sensitive reverse transcriptase polymerase chain reaction (rtPCR) assays) & stays this way for many years

• CD4+ T cell counts steadily decline during this clinical latency period, because of – active viral replication and – T cell destruction in lymphoid tissues

• As the level of CD4+ T cells falls, there is increasing risk of infection and other clinical components of AIDS

[See next slide, Fig 12-10 ]

The clinical course of HIV disease

Fig 12-10