1. Medical Microbiology & Immunology
Guri Tzivion, PhD
Extension 506
BCHM 306: January 2015
Windsor University School of Medicine

2. Questions on tolerance and autoimmune disorders?

3. Central and peripheral tolerance
The fate of lymphocytes that recognize self antigens in the generative organs is death (deletion),
Some B cells may change
their specificity (called
“receptor editing”)
Some CD4 T cells may
differentiate into
regulatory (suppressive)
T lymphocytes

4. Peripheral tolerance Normal T cell response Anergy Apoptosis
APC
CD28
Normal T cell
response
Activated
T cells
TCR
APC
Functional
unresponsiveness
Anergy
Off signals
TCR
Activated
T cell
APC
Apoptosis
(activation-induced
cell death)
Deletion
APC
Suppression
Block in
activation
Regulatory
T cell

5. Tissues affected by autoimmune diseases

6. BCHM 306 MDIII Immunology Class 7 Cancer Immunity and immunodeficiency

7. Cancer Immunity

8. Cancer and Carcinogenesis
Cancers consist of a single or multiple clones of cells capable of uncontrolled proliferation.
Increased proliferation of the cancer cells can form tumors at the origination site or also at distant sites in the case of metastatic cancers.
Cancer cells arise from normal cells via neoplastic transformation or carcinogenesis that involves multiple steps including increased proliferation and evasion from immune surveillance.

9. Cancer pathogenesis
The transformation process involves the activation or deregulation of genes that regulate cell growth, bypassing normal regulatory control mechanisms.
Usually multiple genes must be deregulated for the development of fully malignant tumors and involves the gradual accumulation of transforming mutations
Physical, chemical and biological agents can promote cancer formation, as well as genetic predesposition, however, the large majority of cancers originate from natural random mutations

10. Cancer types and classifications
Carcinomas: epithelial origin involving the skin, mucous membranes, epithelial cells in glands etc.
Sarcomas: cancer of connective tissue.
Lymphomas: T or B cell, Hodgkin’s, Burkitt’s lymhomas. Can involve also solid tumors
Leukemias: disseminated tumors - may be lymphoid or myeloid.

11. Cancer incidents in the UK (2011)

12. Cancer incidents in the UK (2011)

13. Common carcinogens
In general, carcinogens are agents that can increase the rate of mutations or DNA damage and promote cancer formation or progression.
Radiation: any type that has ionizing potential including, Ultraviolet light, X and g-rays, or other radioactive elements.
Chemicals: smoke and tar (cigarettes), chemicals that damage DNA (mutagens), oxygen radicals.
Oncogenic viruses: insert DNA or cDNA copies of viral (v) oncogens into the genome of host target cells.
Hereditary: certain oncogenes/tumor suppressors are inheritable.

14. Tumor Immunology Immune reactivity against tumors
Changes in cellular characteristics due to neoplastic transformation
Inflammatory processes involved in tumor progression or initiation
Use of tumor antigens in diagnosis, prognosis or therapy

15. Oncogenesis carcinogen results in mutation increased GF
increased GF receptors
proto-oncogenes
oncogenes
exaggerated response to GF
tumor
suppressor
genes
loss of ability to
repair damaged
cells or induce
apoptosis
dysfunctional
tumor suppressor
genes
inherited
defect

16. Mechanisms of tumor activation

17. p53 is a common tumor suppressor mutated or deleted in nearly 50% of all human cancers

18. Common traits of cancer cells
Modified intercellular and intracellular signaling processes
Increased proliferation rates
Increased mobility of cells
Increased invasive capabilities and ability to metastasize
Ability to evade the immune system

19. Tumor Surveillance
Involves both the innate immune system and the adaptive immune system
Macrophages and dendritic cells can attack tumor cells based on specific antigens (AB mediated-ADCC) or based on other changes.
CD8 T cell-mediated cytotoxicity
Natural killer cells

20. Common tumor-associated antigens
Human Chorionic Gonadotropin (HCG)
Alpha Fetoprotein (AFP)
Prostate Specific Antigen (PSA)
Mucin CA 125 (glycoprotein molecules on both normal epithelium and carcinomas)
Carcinoembryonic Antigen (CEA)

21. Tumors can both activate and suppress the immune system
Tumors can activate the immune system activley, for example by producing inflammatory cytokines or via expression of foreign/mutated antigens or suppress the immune response through release of inhibitory factors or activation of T regulatory cells that release IL-10 and TGF.

22. Dendritic cells and macrophages present tumor antigens to CD4+ T-cells
Tumor cell or tumor derived antigen
MAC
Dendritic cells and macrophages present tumor antigens to CD4+ T-cells
MAC
MHC II
IL-1
Interferon
T helper Memory cell
T helper cell
IL-2
T helper effectorcell
Macrophages and dendritic cells can directly attack tumor cells or present tumor-specific antigens to CD4 T-cells

23. Cytotoxic T Cell Activity in Tumor Surveillance
memory T cells
MAC or
B cell
(APC)
cytotoxic T cell
MHC 1
cytotoxic
effector T cells
Cancer antigen
Perforins, apoptotic signals
Cancer Cell
cytotoxic T cell

24. APC Tumor antigen or tumor cell cytotoxic memory T cells MAC
cytotoxic T cell
MHC I
APC
cytotoxic
effector T cells
MHC II
IL-1
Interferon
Memory Th cell
Helper 1 T cell
IL-2
Perforins, apoptotic signals
EffectorTh cell
Cancer Cell
cytotoxic T cell
Helper 2
T cell
IL-4
IL-5
Endogenous antigen
Generally ineffective tumor surveillance, but some ADCC
B Cell
Eosinophil

25. NATURAL KILLER CELL
Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” that is common in cancer. NK
Target cell (infected or cancerous)
Perforin apoptotic signals
killer activating receptor

26. Tumor Escape Mechanisms
Low immunogenicity
Antigen modulation
Immune suppression by tumor cells or T regulatory cells
Induction of lymphocyte apoptosis
Lack of MHCI production can render cancer cells “invisible” to CD8 cells

27. Tumor Escape Mechanisms

28. Tumors can escape immune surveillance through natural selection of resistant clones that generate due to genetic instability

29. Immunoediting of cancer cells
Elimination refers to effective immune surveillance for clones that express TSA
Equilibrium refers to the selection for resistant clones (red)
Escape refers to the rapid proliferation of resistant clones in immune competent host

30. Avoidance of tumor surveillance through release of immune suppressants1 2
1) Tumor cells can produce immune suppressants such as TGF- 2) Tumor cells can recruit regulatory T cells, which can suppress the immune response

31. Tumor cells can induce apoptosis in T lymphocytes via FAS activation
Cancer cells express FAS ligand
Binds to FAS receptor on T lymphocytes leading to apoptosis

32. Approaches for cancer immunotherapy
Cytokine manipulations
Tumor vaccines
Serotherapy
Adoptive immunotherapy

33. Tumor Vaccines Killed tumor cells Purified tumor antigens DNA vaccines
Dendritic cell vaccines

34. SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens

35. Immunodeficiency

36. Immunodeficiency Disorders
Immunodeficiency disorders can be induced by
Natural/genetic defects and impairment of the immune function OR
Can be induced through infections or other environmental factors

37. Immunodeficiency Diseases
Primary: Usually congenital, resulting from genetic defects in some components of the immune system.
Secondary(Acquired): as a result of other diseases or conditions such as:
HIV infection
malnutrition
immunosuppression

38. Primary Immunodeficiency Diseases
Can occur because of defects at any one of the
many steps during lymphocyte development

39. Manifestations:
Disorders are manifested at different levels including:
B cell, T cell, phagocytic cells and complement system.
Most prominent manifestations: dermatological conditions such as eczema and cutaneous infections.

40. Symptoms: Recurrent respiratory infections.
Persistent bacterial infections →sinusitis, otitis and bronchitis.
Increased susceptibility to opportunistic infections and recurrent fungal yeast infections.
Skin and mucous membrane infections.
Resistant thrush, oral ulcers and conjunctivitis.
Diarrhea and malabsorption.
Delayed or incomplete recovery from illnesses.

41. Classification of Primary IDDs
Primary B cell immunodeficiency:
X-linked Agammaglobulinaemia (Bruton,s disease) Selective IgA deficiency
Primary T cell immunodeficiency:
Di George syndrome
Ataxia – telangiectasia
Wiskott – Aldrich syndrome
Acquired immunodeficiency
Chemotaxis deficiency
Chronic granulomatous disease
Chediak – Higashi syndrome
Leukocyte adhesion deficiency
Complement system deficiency

42. Etiology Etiology associated with Genetic defects or missing enzymes.
Specific development impairment (pre- B-cell failure).
Infections, malnutrition and drugs

43. Primary B Cell Immunodeficiency
Common variable immunodeficiency associated with
Mature B cells failure to differentiate into mature plasma secreting cells (antibody forming cells).

44. X-linked Agammaglobulinaemia (XLA)/Bruton’s Disease
Deficiency of B cell tyrosine kinase causing a failure in the progression of pre-B cells to maturation.
Majority of XLA patients show:
Profound hypogammaglobulinaemia involving all immunoglobulin classes with <1% B cells than the population.

45. Clinical presentations of Bruton’s disease
Increased susceptibility to encapsulated recurrent infections of pyogenic bacteria (S. pneumonia and pseudomonas species).
Skin infections (group A streptococci and S. aureus).
Persistent viral and parasitic infections.

46. Selective IgA deficiency (IgA D)
Patients with IgA deficiency have:
IgA levels < 5mg/dL with normal levels of other Igs and
50% have chronic otitis, sinusitis or pneumonia.
IgA committed B lymphocytes:
Fail to mature into IgA-secreting plasma cells caused by intrinsic B cell defect.

47. Patients with IgA deficiency are susceptible to:
Allergic conjunctivitis, urticaria and asthma.
Autoimmune and neurological disorders.
Various gastrointestinal diseases (food allergy).
recurrent sinopulmonary infections.

48. Severe Combined Immunodeficiency Disease (SCID)
Disorder characterized by:
Deficiency in both B and T lymphocyte functions with markedly low IgG, IgA and IgE levels.
SCID is associated with:
Children’s failure to thrive.
Chronic respiratory infections.
Gastrointestinal an cutaneous infections, particularly recurrent viral, bacterial, fungal and protozoan infections in the first 6 months.

49. SCID manifests early with:
Persistent and recurrent diarrhea, otitis, thrush and respiratory infections in the first few months of life.
T cell defects associated with:
Candidiasis, CMV infection, measles and varicella leading to life threatening pneumonia, meningitis and sepsis.
SCID can be managed through Ig infusion, stem cell transplantation and gene replacement.

50. T Cell Immunodeficiency Diseases
T cell congenital disorders display:
Little or no cell mediated immunity and may involve B cell deficiencies.
Patients particularly susceptible to:
Repeated fungal (Candida) infection.
Protozoan and viral infections.

51. Primary T cell immunodefiency includes:
Di-George syndrome
Wiskott-Aldrich syndrome
Cartilage hair hypoplasi,
Ataxia - telangiectasia
Defective expression of class II MHC molecules
Defective expression of CD3-T cell receptor (TCR) complex

52. Di George Syndrome (Thymic Aplasia)
Congenital disorder characterized by:
Lack of embryonic development or underdevelopment of the 3rd and 4th pharyngeal pouches.
Thymic hypoplasia, hypothyroidism and congenital heart disease.
Patients susceptible to uncontrolled opportunistic infections.
Impaired in cellular mechanisms.
Profound lymphopenia.

53. Wiskott-Aldrich Syndrome (WAS)
An X-linked recessive disorder associated with thyrombocytopenia and eczema.
Patients have
Elevated IgA and IgE
Low IgM
Variable T cell dysfunctions manifested in:
Severe herpes virus and Pneumocystis carinii infections
Increased lymphomas and autoimmune diseases.
Recurrent pyogenic bacterial infections.
Usually affecting ears, sinuses and lungs.

54. Ataxia Telangiectasia (AT)
Autosomal recessive progressive neurodegenerative childhood disorder associated with:
Lack of coordination (cerebella ataxia) and dilation of facial blood vessels (telangiectasis) and slurred speech.
Patients have defective mechanisms of DNA repair and are predisposed to leukaemias and lymphomas.
Extremely sensitive to radiation exposure and susceptible to chronic respiratory infections.