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

Questions on tolerance and autoimmune disorders?

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

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

Tissues affected by autoimmune diseases

BCHM 306 MDIII Immunology Class 7 Cancer Immunity and immunodeficiency

Cancer Immunity

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.

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

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.

Cancer incidents in the UK (2011)

Cancer incidents in the UK (2011)

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.

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

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

Mechanisms of tumor activation

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

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

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

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)

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.

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

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

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

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

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

Tumor Escape Mechanisms

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

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

Avoidance of tumor surveillance through release of immune suppressants 1 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

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

Approaches for cancer immunotherapy Cytokine manipulations Tumor vaccines Serotherapy Adoptive immunotherapy

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

SEROTHERAPY: Monoclonal Antibodies To Tumor Antigens

Immunodeficiency

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

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

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

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.

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.

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

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

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

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.

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.

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.

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

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.

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.

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.

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

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.

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.

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.