Post on 17-Jan-2016
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