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IMMUNODEFICIENCIES
AND TUMOR IMMUNOLOGY
14th week, 2014
BSc in Public Health
IMMUNODEFICIENCIES
AGE AND HEALTH DEPENDENT
IMMUNOSUPPRESSIVE DRUGS
• INHERITED (PRIMARY) • ACQUIRED
– 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
– Due to infectious
diseases
• AIDS
• Other viral infections
– Malnutrition
– Artificial
immunosuppression
• Drugs
• Radioactive irradiation
PRIMARY IMMUNODEFICIENCIES
• 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
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 DEFICIENCY
recurrent sinopulmonary and
GI infections beginning after
3-4 months
– B cell development
• X-Linked
Agammaglobulinaemia
– hyper IgM syndrome
• CD40L – X-linked
• AID – autosomal
T CELL DEFICIENCY
opportunistic 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)
– CVID
– selective IgA deficiency
• DiGeorge syndrome
– lacking thymus epithelial
cells (aberrant embrional
development)
B CELL
IMMUNODEFICIENCIES
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
Flow cytometric measurement
of peripheral blood leukocytes
CD3 = cell surface marker expressed by T cells
CD19 = cell surface marker expressed by B cells
DEFECT IN T CELL FUNCTIONS
T cells are involved in all aspects of adaptive immunity
SEVERE COMBINED IMMUNODEFICIENCY
(SCID) (Over 50% of T cell deficiencies)
•
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)
TYPES OF INHERITED IMMUNODEFICIENCIES 2.
• 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
TUMOR IMMUNOLOGY
GLOBAL MORTALITY RATE
What is cancer?
Normal tissue
Benign tumor
Cancer
Most frequent sites of tumors
Lungs
Liver
Stomach
Colon
Pancreas
GENERATION OF TUMORS
• if mutations accumulate in tissue cells they may become tumorous
cells:
1.
2.
gain of function mutations of proto-oncogenes that lead to enhanced
proliferation signals
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 TUMORS
Hidden, changing, proliferating, evolving target
TUMOR ANTIGENS
Tumor associated antigens – TAA
Present also in normal cells
Aberrant/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 DC
Cross-presentation
INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE
REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND TLYMPHOCYTES
TNF
IFN
APOPTOTIC
TUMOR CELL
CD40
CD40L
CD40
PS
CD4+
TH1
CD40L
IL-2
HSP
Carbohydrate
APC
DC
MHCII
IL-12
IL
- 12
Oxidation
ICAM-3
M
H
CI
TUMOR
CROSS PRIMING
IFN
Tumor Ag
CD8+
Tc
B
ESCAPE MECHANISMS OF TUMORS
production of soluble MIC  inhibition of killing by NK cells
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) Tcells, which turn off the inflammatory
reaction.
BIOLOGIC TUMOR THERAPIES
UNCONJUGATED
MONOCLONAL
ANTIBODIES
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.
CONJUGATED MONOCLONALS
Treating cancer with immunotherapy
immunotherapy
(breaking the tolerance!)
primary
tumor
metastases
Tumor vaccines
tumor antigen
DC
surgical
removal of
the primary
tumor
adjuvant
DC therapy
CTL
DC + tumor Ag
DC therapy
monoclonal antibodies
Tumor specific
CTL