3Central and peripheral tolerance The fate of lymphocytes that recognize self antigens in the generative organs is death (deletion),Some B cells may changetheir specificity (called“receptor editing”)Some CD4 T cells maydifferentiate intoregulatory (suppressive)T lymphocytes
4Peripheral tolerance Normal T cell response Anergy Apoptosis APCCD28Normal T cellresponseActivatedT cellsTCRAPCFunctionalunresponsivenessAnergyOff signalsTCRActivatedT cellAPCApoptosis(activation-inducedcell death)DeletionAPCSuppressionBlock inactivationRegulatoryT cell
8Cancer 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.
9Cancer pathogenesisThe 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 mutationsPhysical, chemical and biological agents can promote cancer formation, as well as genetic predesposition, however, the large majority of cancers originate from natural random mutations
10Cancer 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 tumorsLeukemias: disseminated tumors - may be lymphoid or myeloid.
13Common carcinogensIn 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.
14Tumor Immunology Immune reactivity against tumors Changes in cellular characteristics due to neoplastic transformationInflammatory processes involved in tumor progression or initiationUse of tumor antigens in diagnosis, prognosis or therapy
15Oncogenesis carcinogen results in mutation increased GF increased GF receptorsproto-oncogenesoncogenesexaggerated response to GFtumorsuppressorgenesloss of ability torepair damagedcells or induceapoptosisdysfunctionaltumor suppressorgenesinheriteddefect
17p53 is a common tumor suppressor mutated or deleted in nearly 50% of all human cancers
18Common traits of cancer cells Modified intercellular and intracellular signaling processesIncreased proliferation ratesIncreased mobility of cellsIncreased invasive capabilities and ability to metastasizeAbility to evade the immune system
19Tumor SurveillanceInvolves both the innate immune system and the adaptive immune systemMacrophages and dendritic cells can attack tumor cells based on specific antigens (AB mediated-ADCC) or based on other changes.CD8 T cell-mediated cytotoxicityNatural killer cells
20Common 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)
21Tumors 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.
22Dendritic cells and macrophages present tumor antigens to CD4+ T-cells Tumor cell or tumor derived antigenMACDendritic cells and macrophages present tumor antigens to CD4+ T-cellsMACMHC IIIL-1InterferonT helper Memory cellT helper cellIL-2T helper effectorcellMacrophages and dendritic cells can directly attack tumor cells or present tumor-specific antigens to CD4 T-cells
23Cytotoxic T Cell Activity in Tumor Surveillance memory T cellsMAC orB cell(APC)cytotoxic T cellMHC 1cytotoxiceffector T cellsCancer antigenPerforins, apoptotic signalsCancer Cellcytotoxic T cell
24APC Tumor antigen or tumor cell cytotoxic memory T cells MAC cytotoxic T cellMHC IAPCcytotoxiceffector T cellsMHC IIIL-1InterferonMemory Th cellHelper 1 T cellIL-2Perforins, apoptotic signalsEffectorTh cellCancer Cellcytotoxic T cellHelper 2T cellIL-4IL-5Endogenous antigenGenerally ineffective tumor surveillance, but some ADCCB CellEosinophil
25NATURAL KILLER CELLDo 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.NKTarget cell (infected or cancerous)Perforin apoptotic signalskiller activating receptor
26Tumor Escape Mechanisms Low immunogenicityAntigen modulationImmune suppression by tumor cells or T regulatory cellsInduction of lymphocyte apoptosisLack of MHCI production can render cancer cells “invisible” to CD8 cells
28Tumors can escape immune surveillance through natural selection of resistant clones that generate due to genetic instability
29Immunoediting of cancer cells Elimination refers to effective immune surveillance for clones that express TSAEquilibrium refers to the selection for resistant clones (red)Escape refers to the rapid proliferation of resistant clones in immune competent host
30Avoidance of tumor surveillance through release of immune suppressants 121) Tumor cells can produce immune suppressants such as TGF- 2) Tumor cells can recruit regulatory T cells, which can suppress the immune response
31Tumor cells can induce apoptosis in T lymphocytes via FAS activation Cancer cells express FAS ligandBinds to FAS receptor on T lymphocytes leading to apoptosis
32Approaches for cancer immunotherapy Cytokine manipulationsTumor vaccinesSerotherapyAdoptive immunotherapy
36Immunodeficiency Disorders Immunodeficiency disorders can be induced byNatural/genetic defects and impairment of the immune functionORCan be induced through infections or other environmental factors
37Immunodeficiency 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 infectionmalnutritionimmunosuppression
38Primary Immunodeficiency Diseases Can occur because of defects at any one of themany steps during lymphocyte development
39Manifestations: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.
40Symptoms: 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.
41Classification of Primary IDDs Primary B cell immunodeficiency:X-linked Agammaglobulinaemia (Bruton,s disease) Selective IgA deficiencyPrimary T cell immunodeficiency:Di George syndromeAtaxia – telangiectasiaWiskott – Aldrich syndromeAcquired immunodeficiencyChemotaxis deficiencyChronic granulomatous diseaseChediak – Higashi syndromeLeukocyte adhesion deficiencyComplement system deficiency
42Etiology Etiology associated with Genetic defects or missing enzymes. Specific development impairment (pre- B-cell failure).Infections, malnutrition and drugs
43Primary B Cell Immunodeficiency Common variable immunodeficiency associated withMature B cells failure to differentiate into mature plasma secreting cells (antibody forming cells).
44X-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.
45Clinical 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.
46Selective IgA deficiency (IgA D) Patients with IgA deficiency have:IgA levels < 5mg/dL with normal levels of other Igs and50% have chronic otitis, sinusitis or pneumonia.IgA committed B lymphocytes:Fail to mature into IgA-secreting plasma cells caused by intrinsic B cell defect.
47Patients with IgA deficiency are susceptible to: Allergic conjunctivitis, urticaria and asthma.Autoimmune and neurological disorders.Various gastrointestinal diseases (food allergy).recurrent sinopulmonary infections.
48Severe 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.
49SCID 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.
50T 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.
51Primary T cell immunodefiency includes: Di-George syndromeWiskott-Aldrich syndromeCartilage hair hypoplasi,Ataxia - telangiectasiaDefective expression of class II MHC moleculesDefective expression of CD3-T cell receptor (TCR) complex
52Di 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.
53Wiskott-Aldrich Syndrome (WAS) An X-linked recessive disorder associated with thyrombocytopenia and eczema.Patients haveElevated IgA and IgELow IgMVariable T cell dysfunctions manifested in:Severe herpes virus and Pneumocystis carinii infectionsIncreased lymphomas and autoimmune diseases.Recurrent pyogenic bacterial infections.Usually affecting ears, sinuses and lungs.
54Ataxia 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.