BSCI 422 - 19. Immunodeficiency and Immunosuppression

Primary immunodeficiency

defect in immune responses as a result of mutation in one or more immunologically important genes

• Inherited immunodeficiency

Secondary immunodeficiency

impaired immune response due to extrinsic factors

• Acquired immunodeficiency

Immunosuppression

intentional induction of immunodeficiency

Detecting immunodeficiency

• Generally found during childhood

  • Patients present with chronic infection, organs of the same or similar type

• Nature of recurrent infection

  • Fives glues to type fo immunodeficiency

• Test implicated components of immune system for and presence and/or function

Complement protein deficiencies

• Mutation in gene for specific complement component

• Most affect complement opsonin function

  • Susceptibility to pyogenic (pus causing) extracellular bacteria

    • Streptococcus spp. and staphylococcus spp (complement required for phagocytosis)

• Defects in MAC components (C5-C9) lead to selective susceptibility to Neisseria spp. Infections (importance of complement-mediated killing of infected cells)

extracellular bacteria

Bacteria that exist outside of host cells and can cause infections, often relying on immune system components for clearance.

• Streptococcus spp. and staphylococcus spp (complement required for phagocytosis)

B cell deficiency

• B cells absence, reduced, or fail to become activated

• Result

  • absent or reduced serum Ig, or deficiencies in select Ig isotypes

  • Defects in responses to extracellular bacteria (lie complement defects) and viruses

Burton’s X-linked Agammaglobulinemia

• B cell deficiency

• block in B cell development, no peripheral B cells, no serum Ig

  • First ever described immunodeficiency

Hyper-IgM syndromes

• B cell deficiency

• defects in B cell activation and class switching

  • Essentially, LOTS of IgM, but little to no IgA, IgG, or IgE

X-linked Hyper IgM

Hyper-IgM syndromes

• Caused by CD40L mutation; some T and Mo defects

Autosomal hyper IgM

Hyper-IgM syndromes

• Caused by mutation in AID (Activation induced cytosine deaminase)

  • AID - enzyme involved in class switching and somatic hypermutation

Selective immunoglobulin deficiencies

• B cell deficiency

• Selective IgA deficiency

• Common variable immunodeficiency - IgM, IgG, and IgA deficiencies

T cell deficiencies

• T cells absent or reduced or selective loss of one class (CD4 vs CD8); or failure to activate T cells

• Result

  • defects in cell-mediated immunity

  • often lead to severe combined immunodeficiency (SCID) (due to role of T cells in B cell function)

SCID

A group of genetic disorders characterized by the absence or dysfunction of T cells and often B cells, leading to severe immunodeficiency and increased susceptibility to infections.

• increased susceptibility to all classes of pathogen

X-Linked SCID

• T cell deficiencies

• yc chain defect; early block in T cell development, so no peripheral T cells

Bare Lymphocyte Syndromes

• T cell deficiencies

• lead to loss of MHC molecule expression

• defect in

  • TAP gene

  • OR

  • RF gene

TAP gene defect

• Prevent MHC Class I protein surface expression

  • No CD8+ T cells

    • mild immunodeficiency

      • Respiratory and skin infections

RF control Defect

• leads to defective MHC class II gene expression (CIITA, RFXANK, RFX5, RFXAP)

  • block CD4+ T cell development

    • SCID

DiGeorge’s syndrome

• T cell deficiencies

• TBX1 deletion

  • Single copy deletion of TF T-Box1 leads to thymic epithelium development

    • Haploinsufficiency

    • Nude mouse

Other T cell deficinecies

• Defects in T cell signaling molecules

  • CD3 components

  • ZAP-70

• Defects in Cytokine expression, cytokine receptors, or cytokine signaling molecules

  • IL-7

Both B/T cell deficiencies

• Some forms of SCID result in lack of both B and T cells due to mutations in genes required for development in both

• ADA and PNP defects affect purine degradation

  • NO B or T cells

  • Most common Autosomal SCID

Autosomal SCID

• Both B/T cell deficiencies

• defects in DNA repair enzymes

• Lead to unreparied double strand breaks during TCR and BCR locus rearrangement

• B and T cell precursors Die

Ataxia telangiectasia

• Both B/T cell deficiencies

• ATM defect

• Protein involved in signaling presence of DNA double strand breaks

• Failure to induce DNA repair machinery during T and B cell development

Phagocyte deficiencies

• Phagocytic cells are critical for immune responses to bacteria, and defects lead to severe susceptibility to bacterial infection

• Neutropenia

Neutropenia

reduced number of neutrophils

Severe congenital neutropenia

• Phagocyte deficiency

• Can be dominant or recessive

• Sutrophil counts are persistently less than 10% of normal

• Fatal without bone marrow transplant

Cyclic neutropenia

• Phagocyte deficiency

• neutrophil elastase mutations

  • Neutrophil numbers cycle between normal to very low/none over 21 day period

  • Other hematopoietic cells have similar, but less severe fluctuations

Leukocyte adhesion deficiency syndrome

• Phagocyte deficiency

• Defect in integrin common B2 subunit CD18

Chromic granulomatous diseases

• Defects in intracellular killing mechanisms

• Caused by defects in NADPH oxidase system (failure to make superoxide radical)

• Intracellular and extracellular infection

• granulomas

G6PD deficiency

• Defects in intracellular killing mechanisms

• Defective respiratory burst, chronic infection

Myeloperoxidase deficiency

• Defects in intracellular killing mechanisms

• Defective intracellular killing

  Chronic infection

Chediak-Higashi syndrome

• Defects in intracellular killing mechanisms

• Caused by defect in lysosome-phagosome fusion

  intracellular and extracellular infection

  granulomas

Cytokine defects

• Mutations in IL-12, IL12R, of IFN-yR lead to susceptibility to non-pathogenic intracellular bacteria

  • Mycobacterium sp. and salmonella spp.

intracellular bacteria

Bacteria that invade and replicate within host cells, often evading the immune system.

• Mycobacterium sp. and salmonella spp.

X-linked lymphoproliferative syndrome

• Cytokine defect

• SAP defect

• Defective control of epstein bar virus (cause of mononucleosis) leads to B cell hyperproliferation, liver necrosis, and death

SAP

• A protein involved in regulating IFN-y production by T cells in response to EBV infection

• defect causes: X-linked lymphoproliferative syndrome

Bone-marrow transplantation (BMT)

requires at least 1 MHC allele in common between graft and patient

problems:

• GVHD

• HVGD

GVHD

graft vs host disease

• Mature T cells in the bone marrow graft attack the patient’s tissues (due to alloreactivity)

  • Mature T cells from graft recognize host cell as foreign

HVGD

host vs graft disease

• Graft is rejected by the patient’s mature T cells and/or NK cells

  • Mature T cells in host recognize graft cells as foreign

Gene therapy

replace defective gene in patient’s own lymphocytes or hematopoietic stem cells

• Limited success with ADA gene therapy using mature lymphocytes or cord blood (HSCd)

• Better success with X linked SCID and retroviral transduction of bone marrow

  • Involves leukemia risk however

Malnutrition

• Secondary immunodeficienciy

• General immunosuppression

• Associated with

  • Lethal measles

  • Tuberculosis

• Links to endocrine system (steroids, leptin)

Diabetes

• secondary immunodeficiency

• A metabolic disorder characterized by high blood sugar levels due to inadequate insulin production or insulin resistance

• Associated with immunosuppression

Hematopoietic tumors

• Secondary immunodeficiency

• (leukemias and lymphomas)

  • Cause immunodeficiency due to neutrophil dysfunction or destruction of lymphoid tissues

Medical interventions

• Secondary immunodeficiency

• chemotherapies/radiation therapy (kill bone marrow derived cells)

• Implanted medical devices lack innate immune responses and serve as sites of immune privilege for opportunistic infections

AIDS

• Secondary immunodeficienciy

• depletion of CD4+ T cells by HIV infection