Immunodeficiency Disease

What autosomal recessive disorders are associated with SCID?

-ADA deficiency (T cells) -PNP deficiency (T-cells) -Bare-Leukocyte syndrome Class 1 or Class II HLA molecules TAP genes (impaired antigen presentation to CD8+ Tcells) -RAG deficiencies (necessary for proper genetic rearrangement)

Severe combined immunodeficiency disease

-An immune disease in which the lymph nodes lack both B lymphocytes and T lymphocytes -Bubble boy

Activation-Induced cytidine deaminase deficiency

-B cells unable to exhibit class switching or affinity maturation -IgM only

What different immunodeficiency defects are there?

-Complement immunodeficiencies or abnormalities that can affect several or individual complement components. (~2-4%) -Phagocytic cell dysfunctions (~15%) -B cell (antibody) immunodeficiency diseases (~50%) -T cell immunodeficiency disease (~30-40%) -Immunodeficiencies can also be caused by or become secondary to other immune dysfunctions

What are the deficiencies in cell-mediated immunity?

-Digeorge's syndrome -Mucocutaneous Candidiasis -Acquired immunodeficiency syndrome (AIDS)

What influences can result in B and T cell immunodeficiencies?

-Direct influences (blocks in development) -Indirect influences (blocks in regulation)

CD4+ ----> TH1

-Inflammatory T cells (IL-2 & TNFa) -----> prominent role in cell mediated immunity -----> delayed hypersensitivity, macrophage activation, CTL activation, some antibody influences ----> Resistance to intracellular infection

What are the phagocytic dysfunctions?

-Leukocyte Adhesion Deficiency -Chronic granulomatous Disease the number of white blood cells are high

RAG deficiencies

-RAG deficiences (recombinant rearrangement) is necessary for the proper genetic rearrangements required for production of the antigen receptors on B and T lymphocytes

Adenosine Deaminase Deficiency

-SCID -No immunity to bacteria, viruses, fungi, parasites -buildup of adenosine - toxic to T-cells -> SCID

What tools are used for monitoring the course of HIV infection?

-Screening for HIV seropositivity (ELISA assay) -Tests for presence of HIV genome (PCR) -Tests for circulating levels of CD4+ (immunofluorescence with monoclonal antibodies

What deficiencies are associated with antibody production?

-X-linked congenital agammaglobulinemia -Common variable immunodeficiency -X-linked hyper-IgM syndrome -Activation-induced cytidine deaminase deficiency

Which therapeutic strategies are used for SCID?

-combinations of antibiotic treatments, -gamma globulin administration -transplantation (bone marrow, stem cell and/or thymus transplantation)

X-Linked congenital agammaglobulinemias

-defective tyrosine kinase (necessary for appropriate V to DJ joining) -generally present in young boys -pre-B cells may be present, but maturation to immunocompetent B cells is defective

Common modes of transmission

-due to unprotected sexual contact -in contaminated blood or blood products -to babies of AIDS mothers

Normal lymphocyte count

1,000 - 4,800

Normal leukocyte count

4,500 - 10,000

Full blown AIDS

<200/ul

What is the number as opportunistic infections first begin to emerge?

<500/ul

Immunodeficiency Disease

A type of disease that decreases the body's ability to produce an effective immune response.

Cell-mediated immunity

Any adaptive immune response in which antigen-specific effector T cells dominate. It is defined operationally as all adaptive immunity that cannot be transferred to a naive recipient with serum antibody. Cell-mediated immune responses include CD4+ T cell-mediated activation of macrophages that have phagocytosed microbes and CD8+ cytolytic T lymphocyte killing of infected cells.

What is the most common immunodeficiency defect?

B cell (antibody) immunodeficiency disease

What defect are associtated with antibody production?

B cells

What integrin is not properly produced in Leukocyte Adhesion deficiency?

CD18

What receptor does HIV use to bind?

CD4

What associated infections are caused by chronic granulomatous disease?

Chronic bacterial and fungal infectons. Granulomas

Mucocutaneous Candidiasis

Colonization of the mucouse membranes Caused by the yeast Candida albicans -dysfunction of the DTH arm of T cell compartment

Digeorge's Syndrome

Congenital thymic aplasia caused by deletion of a sequence of chromosome 22 during embryonic life; Consequences include immunodeficiency, facial abnormalities, and congential heart disease. -B cells are present but demonstrate variable function due to improper regulation in the absence of function t cells.

What cellular abnormality is associated with Chronic granulomatous disease?

Defective NADPH oxidase. Phagocytes cannot produce O2.

What immune defect is associated with Leukocyte adhesion deficiency?

Defective migration of phagocytes into infected tissues

X-linked hyper-IgM syndrome

Defects in helper T cell-dependent B cell and mac activation caused by a mutation in CD40 ligand

Quantification of a circulating B cell can be assessed by __________?

Determining numbers of Surface Ig positive cells. Normal levels of B cells in blood usually ~20-30% of lymphocytes.

Kaposi's sarcoma

Form of skin cancer frequently seen in acquired immunodeficiency syndrome (AIDS) patients. Consists of brownish-purple papules that spread from the skin and metastasize to internal organs.

CD4+ -----> TH2

IL-4, IL-5, IL-10 -----> prominent role in antibody mediated immunity -----> overall B cell activation, mast cell/eosinophil growth, prominent switching to IgE -----> resistance to extracellular infection and soluble mediators or virulence

What immune defect is associated with chronic granulomatous disease?

Impaired killing of phagocytosed bacteria

Leukocyte Adhesion Deficiency

Improperly produced integrin and leukocytes cannot effectively migrate out of blood vessels; Result is life-threatening infection

Phytohemagglutinin

Mitogen that increases proliferation of peripheral blood lymphocytes

Common Variable Immunodeficiency

Normal numbers of circulating B cells, but a decrease in plasma cells, due to defective B cell maturation; (dec) Ig's, acquired in 20's-30's -autosomal inheritance -Selective isotype deficiencies of any isotope can be observed, often due to either the deletion of particular heavy chain genes, or defective isotype switching mechanisms.

What is the most common CVI?

Selective IgA deficiency

Quantification of a functional B cell can be assessed by __________?

Tests of responsiveness to B cell specific mitogens e.g. Staphylococcal protein A

Antibody-mediated immunity

The production of antibodies by B cells in response to an antigen. Also called humoral immunity.

What is immune impairment?

The result of decreased numbers of CD4+ inducer T-cells, dendritic cells and macrophages

What happens to children with Leukocyte Adhesion Deficiency?

They have recurrent pyogenic infections and problems with wound healing; if they survive long enough, they develop severe inflammation of the gums. Their neutrophils and macrophages cannot migrate into tissues and also, bc CR3 and CR4 are complement receptors as well as adhesion molecules, the cells cannot take up and destroy bacteria opsonized with complement .

True or False The decline can involve both non-adaptive and adaptive(humoral and cellular) immunity resulting in dramatically increased susceptibility to infection.

True

What associated infections are caused by Leukocyte adhesion deficiency?

Widespread infections with capsulated bacteria

What X-linked origin disorders are associated with SCID?

X-linked SCID

Acquired immunodeficiency syndrome

a syndrome caused by the human immunodeficiency virus HIV, that renders immune cells ineffective, permitting opportunistic infections, malignancies, and neurologic diseases to develop; transmitted sexually or through contaminated blood

CD3

all mature T cells

Bare-Lymphocyte syndrome

autosomal recessive; lack of class I or both class I and class II; no positive selection in thymus; no Ag presentation; no CD4+ or CD8+ cells -muted TAP genes resulting in impaired antigen presentation to CD8+ T cells

Multi-potential stem cell

cells making up the continually self-renewing tissues of both adult and developing animals

CD8

cytotoxic T cells

What cellular abnormality is associated with Leukocyte adhesion deficiency?

defective CD18 (cell adhesion molecule)

Approximately 50% of autosomal recessive SCID is the result of an ________ deficiency.

enzyme (ADA & PNP)

Quantification of functional T cells can be assessed by __________?

evaluating T cell responses (such as DTH skin testing) against antigens associated with microorganisms commonly found in our environment T cell proliferation and/or cytokine production can be tested in vitro in response to T cell specific mitogens. (such as Phytohemagglutinin)

Leukocyte adhesion deficiency is associated with persistent infection with __________ bacteria.

extracellular

CD4

helper/inducer T-cells

Chronic granulomatous disease

immunodeficiency caused by a defect in the enzyme NADPH phagosome oxidase resulting in failure to generate reactive oxygen species in neutrophils

Lymphoma

malignant tumor of lymph nodes and lymph tissue

Myeloma

monoclonal antibodies made by fusing B cells with cancer cells

X-linked SCID

no functional B or T cells, bubble boy, defective gamma common chain, defective receptors for IL-2,3,7,9,15,21. 7 - T cell development, 15 - NK cell deficiency

What characteristics are associated with immunodeficiency Disease?

skin rashes, abscesses, chronic diarrhea, abnormal growth, hepatosplenomegaly, thrombocytopenia or endocrinothathies.

Selective IgA deficiency

very low/absent IgA, other classes normal (elevated); increased association with allergies, autoimmunity; susceptibility to respiratory infections caused by encapsulated organisms; no replacement therapy

What is the normal CD4+ T cell landmark?

~1200/ul

What is the number in HIV asymptomatic individuals?

~800/ul