Medical Microbiology & Immunology

Guri Tzivion, PhD

tzivion@windsor.eduExtension 506

BCHM 306: January 2015Windsor University School of Medicine

Questions on tolerance and

autoimmune disorders?

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

Central and peripheral tolerance

APC TCR

T cellCD28

ActivatedT cells

APC TCR

Functionalunresponsiveness

Normal T cellresponse

Anergy

Apoptosis(activation-inducedcell death)APC

Deletion

APC

Block inactivation

Suppression

RegulatoryT cell

Peripheral tolerance

Off signals

ActivatedT cell

Tissues

affected by

autoimmune

diseases

BCHM 306 MDIII ImmunologyClass 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.

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 pathogenesis

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 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.

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

proto-oncogenes

tumorsuppressor

genes

oncogenes

carcinogenresults in mutation

dysfunctional tumor suppressor

genes

inheriteddefect

increased GF

increased GF receptors

exaggerated response to GF

loss of ability torepair damaged cells or induce

apoptosis

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Mechanisms of tumor activation

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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.

MAC

MHC II

MAC

T helper cell

IL-2

T helper Memory cell

T helper effectorcell

IL-1 Interferon

Macrophages and dendritic cells can directly attack tumor cells or present tumor-specific antigens to CD4 T-cells

Tumor cell or tumor derived antigen

Dendritic cells and macrophages present tumor antigens to CD4+ T-cells

MAC or B cell(APC)

MHC 1cytotoxic T cell

Perforins, apoptotic signals

cytotoxicmemory T cells

cytotoxiceffector T cells

Cytotoxic T Cell Activity in Tumor Surveillance

Cancer Cell

cytotoxic T cell

Cancer antigen

MAC

MHC II

MHC IAPC

Helper 1 T cell

Helper 2 T cell

IL-2

B Cell

Eosinophil

IL-4 IL-5

Memory Th cell

EffectorTh cell

IL-1

cytotoxic T cell

cytotoxicmemory T cells

cytotoxiceffector T cellsInterferon

Cancer Cell

cytotoxic T cell

Endogenous antigen

Perforins, apoptotic signals

Generally ineffective tumor surveillance, but some ADCC

Tumor antigen or tumor cell

NATURAL KILLER CELL

NK

Target cell (infected or cancerous)

Perforin apoptotic signalskiller activating receptor

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.

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

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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

1) Tumor cells can produce immune suppressants such as TGF- 2) Tumor cells can recruit regulatory T cells, which can suppress the immune response

1 2

Avoidance of tumor surveillance through release of immune suppressants

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Tumor cells can induce apoptosis in T lymphocytes via FAS activation

1) Cancer cells express FAS ligand

2) 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

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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 DiseasesCan 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 syndromeAtaxia – telangiectasiaWiskott – Aldrich syndromeAcquired immunodeficiencyChemotaxis deficiencyChronic granulomatous diseaseChediak – Higashi syndromeLeukocyte 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.