IMMUNO-

DEFICIENCIES

 

No sufficient level of protective immunity is reached due to inherited (primary)

 or acquired  (secondary) defects of the immune system. 

 

                                         

IMMUNODEFICIENCIES

Serious overwhelming reccurent life-threatening infections ofpredominantly respiratory, GI or skin system.

Defects in phagocytosis or immunoglobulin synthesis:                pyogenic bacterial infections Defects in specific cell-mediated immunity:                viral, fungal or opportunistic infections

CLINICAL    PRESENTATION:CLINICAL    PRESENTATION:

IMMUNODEFICIENCIES

IMMUNODEFICIENCIES

PRIMARYIMMUNODEFICIENCIES

• inherited

• presentation in early infancy

SECONDARYIMMUNODEFICIENCIES

•  acquired

• presentationduring

adulthood

• rare events

• heterogenous group

• with known molecular basis

• both innate and acquired immunity could be affected 

PRIMARY    IMMUNODEFICIENCIES:PRIMARY    IMMUNODEFICIENCIES:

DISTRIBUTION  OF   PRIMARY    IMMUNODEFICIENCIESDISTRIBUTION  OF   PRIMARY    IMMUNODEFICIENCIES

complementphagocytosis

combined andT cell deficiencies

defect in production of antibodies

PHAGOCYTOSIS:

- defects in adhesion (LAD II, I) - defects in chemotaxis - defects in ingestion - defects in killing O2 independent (defensins)

O2 dependent (NADPH oxidase)

COMPLEMENT SYSTEM:

both classical and alternative pathways could be impaired

INNATE IMMUNITY:INNATE IMMUNITY:

ADHESIONLAD II, I

SY.

ADHESIONLAD II, I

SY.

CHEMOTAXISlazy leukocytes sy.CHEMOTAXIS

lazy leukocytes sy.

INGESTIONINGESTIONLACK OFOPSONINSLACK OFOPSONINS

DEFECTS INCYTOSKELETON

DEFECTS INCYTOSKELETON

O2-INDEPENDENTdefensins deficiencyO2-INDEPENDENTdefensins deficiency

O2-DEPENDENTNADPH oxidase defect (CGD)

myeloperoxidase defect

O2-DEPENDENTNADPH oxidase defect (CGD)

myeloperoxidase defect

early componentsof classical

andalternativepathwaysdeficiency

early componentsof classical

andalternativepathwaysdeficiency

deficiency of soluble

regulatory factors

deficiency of soluble

regulatory factors

membrane regulatory molecules deficiency (protectin)

membrane regulatory molecules deficiency (protectin)

COMPLEMENT SYSTEM

PHAGOCYTOSIS

KILLING

PRIMARY IMMUNODEFICIENCIES:PRIMARY IMMUNODEFICIENCIES:

INNATEIMMUNITY

INNATEIMMUNITY

SPECIFIC IMMUNITY:SPECIFIC IMMUNITY:

A) PRIMARY HUMORAL IMMUNODEFICIENCIES

B-cell development and immunoglobulin synthesis is affected.

X-linked agammaglobulinemia (Bruton’s) • mutation in btk gene encoding cellular kinase • absence of B-cells • absence of immunoglobulins

Selective Ig class deficiency:

• IgA deficiency is the commonest

Hyper IgM syndrome:

• high level of IgM

• low levels of other classes of immunoglobulins

• absence of CD40L on T-cells

• inability to switch isotype Ig synthesis

Common Variable ImmunoDeficiency (CVID):

• manifestation in early adulthood

• HLA association (HLA-DR3)

• association with immunopathological diseases

• recurent severe bacterial pneumonia

• hypogammaglobulinemia is a common feature

• probably caused by defects in T, B cell cooperation

B) PRIMARY CELL-MEDIATED DEFICIENCIES:

• absence or malformation of thymus

• lethal viral, fungal or opportunistic infections

• thymic aplasia

• DiGeorge abnormality

C) PRIMARY COMBINED HUMORAL AND CELLULAR DEFICIENCIES:

• both cellular and humoral components

of the immune system are affected

• severe combined immunodeficiency (SCID) is developed

• there are several molecular mechanisms

of SCID development

ADENOSIN DEAMINASE DEFICIENCY (ADA):

• abnormal purine metabolism

• toxic products are accumulated in T and B cells

• T and B cells are killed

• replacement therapy

• first example of gene therapy

γ SUBUNIT OF IL-2 RECEPTOR DEFICIENCY:

• γ subunit is shared by at least receptors for IL-2, IL-4, IL-7, IL-9, IL-13, IL-15

• absence of γ subunit leads to substantial defects in signaling

DEFICIENCIES OF HLA-I OR HLA-II MOLECULES

DEFICIENCY OF ZAP-70 KINASE

DEFICIENCY OF RAG-1, 2 ENZYMES

• any signaling surface or intracellular molecule of leukocytes could be affected by the genetic defects with resulting immunodeficiency

• examples are receptor for interferon γ , IL-12R, production of interferon γ , IL-12, intracellular signaling molecules such as Jak-1 kinase

MISCELLANEOUS PRIMARY IMMUNODEFICIENCIES:MISCELLANEOUS PRIMARY IMMUNODEFICIENCIES:

SPECIFIC IMMUNITY SPECIFIC IMMUNITY

PRIMARY IMMUNODEFICIENCIES (ID)PRIMARY IMMUNODEFICIENCIES (ID)

HUMORAL ID

B lympho, Ig

CELLULAR ID T lympho

RAG 1,2deficiency

ADA deficiency

γ subunitIL-2R

deficiency

CVID

agammaglobulinemia

selectivedeficiency

of Igs

thymic aplasia

INFγR deficiencyWiscott-

Aldrich sy.

hyper IgMsyndrome

HLA I, II deficiency

DiGeorgeanomaly

ataxiateleangiectasia

CD3subunits

deficiency

COMBINED ID (SCID)ZAP-70

deficiency

Jak-1deficiency

• molecular evidence of defects enabled prenatal testing

• immunoglobulin replacement therapy by intravenous immunoglobulins (IVIG)

• bone marrow transplantation

• gene therapy

PRIMARY IMMUNODEFICIENCIES (ID)

CLINICAL NOTES:

PRIMARY IMMUNODEFICIENCIES (ID)

CLINICAL NOTES:

• very heterogenous group of immunodeficiencies according to their origin

• acquired presentation during adulthood

• origin is sometimes not known

CLINICAL PRESENTATION: • chronic infections of respiratory, GI and skin systems

LABORATORY PARAMETERS:

• diminished or absent skin test reactions

• hypogammaglobulinemia

• low level of T-cells and helper T-cells

• low level of lymphocyte proliferation in vitro

SECONDARY IMMUNODEFICIENCIES (ID)SECONDARY IMMUNODEFICIENCIES (ID)

SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH MALIGNANCY:

• most frequent • most profound in the hematological malignancies • hypogammaglobulinemia • defects in phagocytosis • defects in T-cell imunity

SECONDARY IMMUNODEFICIENCIES INDUCED BY DRUGS:

• chemotherapeutics • antiinflammatory drugs (corticosteroids) • antibacterial drugs • abused drugs (coccaine, marihuana)

SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH MALNUTRITION:

• caloric malnutrition

• protein malnutrition

• vitamins and trace elements malnutrition

• vegetarian habit

SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH TRAUMA:

• injury is associated with inflammatory response

• iatrogenic injuries in medicine

SECONDARY IMMUNODEFICIENCIES CAUSED BY INFECTIOUS AGENTS:

• viral infections (herpes simplex, EBV, CMV, rubella, measles, etc.) can cause immune depression

• this immune depression is self-limiting in majority of patients

• HIV infection and AIDS

• development of life-threatening Systemic Inflammatory Response Syndrome (SIRS) induced by infection caused by LPS positive bacteria (septic shock)

• followed by immune system exhaustion (immune depression)