IMMUNODEFICIENCIES AND TUMOR IMMUNOLOGY

14th week, 2014

BSc in Public Health

IMMUNODEFICIENCIESAGE AND HEALTH DEPENDENTIMMUNOSUPPRESSIVE DRUGS

• INHERITED (PRIMARY)– Loss of function mutation of

genes of the immune system

– Enhanced susceptibility to infections

– Particular types of pathogens depending on the gene defect

– Did not show up until 1950 - antibiotics

• ACQUIRED– Due to infectious

diseases • AIDS• Other viral infections

– Malnutrition– Artificial

immunosuppression• Drugs• Radioactive

irradiation

• MOST ARE RECESSIVE MUTATION OF SINGLE GENES

– Dominant traits have been eliminated from the population– Autosomal genes or X-linked genes (different inheritance)

• DOMINANT: Mutation in the IFNγ receptor results in binding without intracellular signaling

DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium (M. bovis) USED FOR VACCINATION

PRIMARY IMMUNODEFICIENCIES

Numerous Immunodeficiency loci reside on the X chromosome

CGD: Chronic Granulomatous Disease

WAS: Wiscott-Aldrich Syndrome

SCID: Severe Combined Immunodeficiency

XLA: X-linked Agammaglobulinemia

XLP: X-linked Lymphoproliferative Disease

XLHM: X-linked Hyper-IgM Syndrome

TYPES OF INHERITED IMMUNE DEFICIENCIES

B CELL DEFICIENCYrecurrent sinopulmonary and GI infections beginning after 3-4 months

– B cell development• X-Linked

Agammaglobulinaemia

– hyper IgM syndrome• CD40L – X-linked• AID – autosomal

– CVID

– selective IgA deficiency

T CELL DEFICIENCYopportunistic infections beginning early in infancy

• SCID– T cell development

• IL-7 signaling defect• RAG-1/2 def. (Omenn’s sy.)• DNA repair enzyme defect• Purin catabolism

(metabolites toxic to developing B and T cells)

– MHC deficiency (Bare Lymphocyte Syndrome)

• DiGeorge syndrome– lacking thymus epithelial

cells (aberrant embrional development)

Approx. 70% of all primiary IDs

Late Manifestation (3-10 months)

Increased sensitivity to epithelial pathogens:• pyogenic bacteria (e.g. streptococci)• GI pathogens (e.g. enteroviruses)

Threatment:

intravenous human immunoglobulin (hIVIG) every month

B CELL IMMUNODEFICIENCIES

Flow cytometric measurement of peripheral blood leukocytes

CD3 = cell surface marker expressed by T cells CD19 = cell surface marker expressed by B cells

• Neither T cell-dependent antibody response nor cellular immunity are functional

• Small body weight, failure to thrive

• Persistent and recurrent infections with a broader range of pathogens than in

patients with B cell deficiencies

• Opportunistic infections (Candida albicans, Pneumocystis carnii)

• Treatment:– Bone marrow transplantation, preferably from a histocompatible sibling

– (Gene therapy)

DEFECT IN T CELL FUNCTIONST cells are involved in all aspects of adaptive immunity

SEVERE COMBINED IMMUNODEFICIENCY(SCID) (Over 50% of T cell deficiencies)

• PHAGOCYTIC SYSTEM– CD18 (CR3, CR4, LFA1)

deficiency aka Leukocyte Adhesion Deficiency (LAD)

• no leukocyte migration to sites of inflammation

– NADPH oxidase deficiency aka Chronic Granulomatous Disease (CGD)

• granuloma formation in case of several infections by intracellular pathogens

– Chédiak-Higashi Syndrome (CHS)

• defect of phagolysosome formation

• COMPLEMENT SYSTEM– pyogenic infections,

primarily with encapsulated microorganisms and Neisseriae

TYPES OF INHERITED IMMUNODEFICIENCIES 2.

TUMOR IMMUNOLOGY

GLOBAL MORTALITY RATE

Normal tissue

Benign tumor

Cancer

What is cancer?

Liver

Lungs

Stomach

Colon

Pancreas

Most frequent sites of tumors

GENERATION OF TUMORS• if mutations accumulate in tissue cells they may become tumorous

cells:1. gain of function mutations of proto-oncogenes that lead to enhanced

proliferation signals

2. loss of function mutations of tumor suppressor genes that inactivate regulation of the cell cycle

• tumor cells are continuously proliferating cells that have genetic instability mutations and chromosomal aberrations accumulate

• invading local tissues– benign: respecting tissue borders (basement membranes)– malignant: spread to all nearby tissues, can even give off metastases

(local ones via the lymph, or distant ones via the blood)

Tumor cells are generated in our bodies daily but normally they are cleared by the immune surveillance

THE IMMUNE RESPONSE TO TUMORSHidden, changing, proliferating, evolving target

TUMOR ANTIGENSTumor associated antigens – TAA

Present also in normal cellsAberrant/dysregulated expression in tumor cells

Tumor specific antigens – TSA Unique for individual tumors or tumor types

IMMUNE SYSTEM

Tumor-specific immune responses can be induced

Cytotoxic T lymphocytes can eradicate tumors

Activation of tumor-specific T-cells by DCCross-presentation

M HC II

CD8+

Tc

IL-12

CD4+

T 1H CD40LCD40L

CD40 B

INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND T-

LYMPHOCYTES

IL-2

IFN

Tumor Ag

CROSS PRIMING

TUMOR

APOPTOTIC TUMOR CELL

PS

OxidationICAM-3

HSP

Carbohydrate

TNFIFN

M HC I

APC

CD40

DC

IL - 12

production of soluble MIC inhibition of killing by NK cells

ESCAPE MECHANISMS OF TUMORS

In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis.

When a cell is transformed into a cancer cell, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells.

It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

BIOLOGIC TUMOR THERAPIES

Antibodies bind to a cell-surface antigen of the tumor cells. The Fc regions of the antibodies engage FcγRIII on an NK cell, which then becomes activated to kill the tumor cell.

UNCONJUGATED MONOCLONAL ANTIBODIES

CONJUGATED MONOCLONALS

tumor antigen

adjuvant

DC + tumor Ag

Tumor specificCTL

DC therapy

DC therapy

Tumor vaccines

primarytumor

metastasessurgical

removal of the primary

tumor

immunotherapy

monoclonal antibodies

Treating cancer with immunotherapy(breaking the tolerance!)

DC

CTL