Immunodeficiency and tumour immunology Flashcards
tut review
What are some of the proteins affected by mutations that may block the maturation of either T and/or B lymphocytes in human immunodeficiency diseases?
see slide 58 diagram
- IL-7 signals (X-linked severe combined immunodeficiency (SCID))
- ADA: adenosine deaminase or PNP: purine nucleoside phosphorylase (Autosomal recessive SCID due to deficiency of these)
- RAG, IL-7R signal (AUtosomal recessive SCID from other causes)
tut review
What are some of the mutations that may block activation or effector functions of both mature CD4+ T cells and B cells?
see slide 68 diagram
Defects that impair B cell activation:
- defect in TCR complex signalling, Class II MHC deficiency –> T cell NOT activated
- CD40 ligand mutation: impairs both macrophage and B cell functions
tut review
How does HIV infect cells and replicate inside infected cells?
HIV infection cycle:
1. virion binds to CD4 and chemokine receptor
2. HIV membrance fuse with cell membrane. viral genome enters cytoplasm
3. reverse transcriptase mediated synthesis of proviral DNA
4. integrations of provirus into cell genome
5. cytokine activationof cell, transcription of HIV genome, transport of spliced and unsolicited RNAs to cytoplasm
6. synthesis of HIV proteins, assembly of virion core structure.
7. expression of gp 120/gp41 on cell surfacce, budding of mature virion
tut review
What are the principal clinical manifestations of advanced HIV infection, and what is the pathogenesis of these manifestations?
a. Clinical manisfestations : AIDS
Opportunistic infections: Candidiasis, Tuberculosis
Other common infections:
- Pneumocystis carinii
- Mycobacterium avium
- Toxoplasma gondii
- Cryptospiridae
AIDS-defining cancers:
- Kaposi’s sarcoma (purple skin patches)
- Non-Hodgkin lymphoma (EBV)
- Cervical cancer (HPV)
The clinicopathologic manifestations of full-blown AIDS are primarily
the result of **increased susceptibility to infections and some cancers, **as a consequence of immune deficiency.
The dementia that develops in some patients is likely caused by
infection of macrophages (microglial cells) in the brain.
Patients with advanced AIDS often have a wasting syndrome with
significant loss of body mass, caused by altered metabolism and
reduced caloric intake, possibly a result of cytokines produced during
repeated and chronic infections.
*Under HIV-induced immunodeficiency, latent HHV-8 virus is activated to cause sarcoma
b. Pathogenesis of AIDS
1. infection of mucosal tissue
2. death of mucosal memory CD4 T cells
3. infection in established lymphoid tissues eg lymph node
4. infection spread throughout body
5. viremia
Anti-HIV immune response & clinical latency (after viremia)
6. partial control of viral replication thru response
7. establishment of chronic infection, virus concentrated in pymphoid tissues, low level virus production
8. increased viral replication from other microbial infections and cytokines
9. AIDS: destruction of lymphoid tissue, depletion of CD4 T cells
tut review
What are the main types of tumor antigens that provoke the immune system?
Gene mutations progressively leads to colon cancer
1. Tumor cells arise from healthy cells
2. Loss of contact inhibition (local invasion/begnign tumor)
3. Gain of adhesion-independent growth (metastasis/malignant cancer)
4. Sequential accumulation of mutations and aberrant expression of normal antigens (immunogenicity)
5. Evasion of the immune system
Mutations accumulate to generate incompletely differentiated, but constitutively proliferating cells
Tumor cells are:
1) Not fully differentiated
2) Lack tissue-specific functions
3) Retain growth potential
4) Survive to accumulate
mutations
tut review
What is the evidence that tumors can be rejected by the immune system?
experimentally….
Transplants of a syngeneic tumor are rejected by animals, and more rapidly if the animals have been previously exposed to that tumor; immunity to tumor transplants can be transferred by lymphocytes from a tumor-bearing animal
Tumor rejection shows features of adaptive immunity (specificity, memory) and is mediated by lymphocytes. Tumor vaccination induces tumor-specific CD8+ memory T cell-mediated tumor eradication and tumor-specific adaptive immunity
tut review
How do naive CD8+ T cells recognize tumor antigens, and how are
these cells activated to differentiate into effector CTLs?
Tumor-specific CD8+ T cells require cross-presentation
of the tumor antigens by dendritic cells
tut review
What are some of the mechanisms by which tumors evade the
immune response? (2)
No tumor antigen is presented by MHC I (to CD8 T cells)
Tumor cells lose MHC I and cannot present tumor antigens
1) tumors express surface Inhibitory receptors
2) Tumor cells secrete inhibitory cytokines
tut review
What are some strategies for enhancing host immune responses
to tumor antigens? (3)
diagram on slide 36
- passive immunity by transferring tumour specific T cells or antibodies
- active T cell immunity enhanced by dendritic cell vaccines
- active immunity enhanced by blockade of T cell inhibitory molecules
Most successful: 3. 1. is adoptive (t cell??)
tut review
How may antibodies be explored to eradicate tumors?
slide 97
- rituximab monoclonal antibody mechanisms against B cell lymphoma (4)
A. NK cell mediated direct killing
B. Complement dependent cytotoxicity (CDC)
C. Antibody-dependent cell cytotoxicity (ADCC)
D. Antibory-dependent phagocytosis (ADP) - Chimeric T cell antigen receptor (CAR-T)
antigen recognition –> Co-stimulatory signal + signalling cascade –> transcription of T cell effector function (IL 2 proliferation, cytotoxicity) –> perforation and granzyme release –> cell death
quiz tumour
MCQ-1: The following features is correct
regarding regulatory T cells:
A) They help B cells in the production of antibodies
B) They represent a part of peripheral immune tolerance
C) They are produced in the bone marrow
D) They activate macrophages with their surface CD40L
E) They kill virus-infected or cancer cells
B
Treg: A population of T cells that regulate the activation or effector functions of other T cells (NOT b cells; A wrong) and may be necessary to maintain tolerance to self antigens. Most regulatory T cells express CD4, CD25 and FoxP3.
C wrong: B cells then is produced in bone marrow. T for thymus
D: helper T activates macrophages, not Treg!
E wrong: this is cytotoxic T cells
quiz tumour
MCQ-2: Which of the following is a commonly used cancer immunotherapy?
A) Cancer vaccines
B) Injection of TNFa
C) Adoptive transfer of B cells
D) Anti-CD20 antibodies
E) Adoptive transfer of dendritic cells
D
1. Inject cytokines: eg IL-2, TNF-a, Interferons -
but all are toxic [B] –> NOT COMMON
2. Tumour vaccines: eg. dendritic cell vaccines,
mRNA vaccines, peptide vaccines
3. Serotherapy eg monoclonal antibodies (e.g. CD19-expressing B cell cancers) [D]
4. Adoptive T cell immunotherapy (I): ex vivo
expanded autologous tumor-infiltrating
lymphocytes (TIL)
5. Adoptive T cell immunotherapy (II) – engineered chimeric antigen receptor T cells (CAR-T)
A does not exist, still in development
C and E wrong: no such thing. only adoptive T cell
quiz immunodeficiency
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) deficiency is MOST LIKELY to
cause:
A) SCID (severe combined immunodeficiency)
B) Cancers
C) Systemic lupus erythematosus (SLE)
D) AIDS
E) Immunoglobulin class switch by B cells
C
A wrong: lack B AND T
B wrong: caused by gene mutation
D wrong: caused by CD4 deficiency
E wrong: it’s not rlly a problem…?
quiz immunodeficiency
MCQ-4: One of the following defects increases immune responses:
A) IL-7
B) CD40L
C) ATM (Ataxia-telangiectasia mutated)
D) Aire
E) MHC class II
D
the rest lead to immunodeficiency
Ataxia-telangiectasia mutated （ATM): required
for optimal BCR and TCR formation
quiz tumour
MCQ-5: One of the following is NOT known to contribute to tumour cell evasion of the immune system:
A) Reduced MHC class I expression
B) Expression of PD-L1
C) Non-oncogenic antigen mutations
D) Activation of oncogenes
E) Inactivation of tumor suppressor genes
C
Mechanisms of tumors evasion of immune responses:
- No tumor antigen is presented by MHC I (to CD8 T cells) [A]
- Tumor cells lose MHC I and cannot present tumor antigens
1) tumors express surface Inhibitory receptors
2) Tumor cells secrete inhibitory cytokines
D and E contributes: recall bio
B: from textbook: tumor cells produce immunosuppressive cytokines or ligands such as PD-L1 for inhibitory receptors on T cells
