IMMU2011 - Weeks 11-12

What is the difference between active and passive immunity?

active: body generates immune response (memory present); passive: preformed antibodies or cells are transferred (no memory)

What are examples of passive immunisation?

convalescent plasma, monoclonal antibodies, antitoxins (e.g., diphtheria antiserum)

What are the mechanisms of action of antibodies in passive immunisation?

neutralisation, opsonisation, complement activation, and ADCC

What is a vaccine and what does it do?

it is a biological product that induces protective immune responses against specific pathogens

How do adjuvants enhance vaccine efficacy?

they boost the immune response by mimicking microbial signals, increasing antigen presentation, and stimulating costimulatory molecules

What are FDA-approved vaccine adjuvants?

aluminium salts, AS04, MF59, CpG 1018

How do different vaccine types work?

mRNA and DNA vaccines encode antigens; recombinant protein vaccines deliver antigens; viral vectors deliver genes; inactivated and live attenuated vaccines present whole pathogens

How does an mRNA vaccine induce immunity to SARS-CoV-2?

host cells produce spike protein, triggering B cell antibody production and T cell responses (CD4+ and CD8+), leading to virus neutralisation and clearance

What causes severe disease in COVID-19?

dysregulated immune response, cytokine storm (especially IL-6), lymphopenia, and ongoing inflammation with minimal viral presence

What are the main types of grafts in transplantation?

autologous (same individual), syngeneic (identical twin), allograft (same species, different individual), xenograft (different species)

What is the role of MHC molecules in transplantation?

MHC (HLA in humans) present antigens and are recognised as "non-self," leading to graft rejection.

What is an HLA haplotype?

A set of HLA alleles inherited together from one parent; each person has two

Why is HLA matching important for transplantation?

minimises graft rejection by reducing recognition of non-self MHC by recipient T cells

What are the three pathways of T cell allorecognition?

direct (recipient T cells recognise donor MHC), indirect (recipient APCs present donor peptides), semi-direct (donor MHC is acquired and presented by recipient APCs)

Why is the alloresponse so strong?

because 1-5% of T cells can recognise allo-MHC directly, compared to <0.01% for conventional antigens

What is hyperacute rejection?

immediate rejection caused by preformed antibodies against donor antigens, leading to complement activation and thrombosis

What is acute rejection?

occurs days to weeks post-transplant; mediated by T cells (direct and semi-direct) and antibodies

What is chronic rejection?

months to years post-transplant; mediated by T cells and antibodies, leading to fibrosis and vascular damage

How do we prevent graft rejection before transplantation?

blood type matching, HLA typing, screening for donor-specific antibodies, and lymphocyte cross-matching

What are the types of cross-match tests used?

complement-dependent cytotoxicity assay and flow cytometry for detecting donor-specific antibodies

What is immunosuppressive therapy used for in transplantation?

to prevent T cell activation and graft rejection; includes induction (e.g., mAbs) and maintenance therapy (e.g., calcineurin inhibitors, steroids)

How is antibody-mediated rejection treated?

plasma exchange, IVIg, steroids, and investigational therapies targeting B cells

What is operational tolerance in transplantation?

stable graft function without immunosuppression; achieved in some liver transplants and bone marrow/kidney co-transplants

How are regulatory T cells being used in transplantation?

Treg therapy is in trials to promote immune tolerance and reduce graft rejection

Why is transplantation difficult despite immunosuppression?

due to extreme HLA polymorphism, strong alloresponse, and challenges in inducing lasting immune tolerance

Define autoimmune response.

an immune response where the body's immune system attacks its own tissues due to loss of tolerance to self-antigens

Define allergic response.

an exaggerated immune reaction to harmless environmental antigens, typically involving a Type I hypersensitivity reaction

What are autoimmune and allergic diseases classified as?

hypersensitivity diseases caused by pathological or excessive immune responses

What immune components are involved in Type I hypersensitivity?

Th2 cells, IgE, mast cells, eosinophils, and basophils

What immune components are involved in Type II hypersensitivity?

IgM and IgG antibodies directed against cell surface or ECM antigens, leading to complement activation and phagocytosis

What characterises Type III hypersensitivity reactions?

formation of immune complexes that deposit in tissues, causing inflammation via complement and Fc receptor activation

What is Type IV hypersensitivity?

T cell-mediated response; involves CD4+ T cell cytokine-mediated inflammation or CD8+ cytolysis of target cells.

What differentiates allergy from autoimmunity?

allergy is a reaction to harmless external antigens (Type I), while autoimmunity is a response to self-antigens (Types II-IV)

What is the definition of autoimmunity?

a specific immune attack against one's own cells or molecules due to loss of self-tolerance

What are organ-specific autoimmune diseases?

autoimmune diseases where the target antigen is restricted to a single organ (e.g., Type 1 diabetes)

What are systemic autoimmune diseases?

diseases where the target antigens are widespread throughout the body (e.g., lupus)

How does the immune system normally prevent autoimmunity?

through central and peripheral tolerance mechanisms that eliminate or suppress self-reactive lymphocytes

Where is central tolerance established?

in the thymus for T cells (deletion or Treg development) and bone marrow for B cells (receptor editing or deletion)

What is peripheral tolerance?

suppression of self-reactive lymphocytes in the periphery via Tregs, anergy, or immune checkpoints

What genetic factor is most strongly associated with autoimmunity?

HLA (Human Leukocyte Antigen) genes, due to their role in antigen presentation to T cells

How do HLA polymorphisms contribute to autoimmunity?

they affect peptide binding, influencing which self-antigens are presented and which T cells are selected during development

What are examples of HLA Class II-associated autoimmune diseases?

SLE, rheumatoid arthritis, multiple sclerosis, Type 1 diabetes

What are examples of HLA Class I-associated autoimmune diseases?

psoriasis, ankylosing spondylitis, psoriatic arthritis

What environmental factors can trigger autoimmunity?

infections, tissue damage, microbiota changes, sex hormones, and regulatory RNA dysregulation

What is molecular mimicry?

an immune response to an infectious agent cross-reacts with structurally similar self-proteins

What is an example of an organ-specific autoimmune disease?

Type 1 diabetes, where immune cells attack pancreatic β cells

What is an example of a systemic autoimmune disease?

systemic lupus erythematosus (SLE), involving autoantibodies to nuclear antigens and widespread inflammation

How is autoimmunity treated?

symptom management (e.g., hormone replacement) and immune modulation with immunosuppressants or biologics

What is an allergy?

an inappropriate immune response (Type I hypersensitivity) to non-harmful environmental antigens (allergens)

What are the major immune players in allergy?

Th2 cytokines (IL-4, IL-5, IL-13), IgE, mast cells, basophils, and eosinophils

What is atopy?

a genetic predisposition to developing allergic diseases

What happens during the sensitisation phase of allergy?

initial antigen exposure induces Th2 response, class-switching to IgE, and IgE binding to mast cell FcεRI receptors

What triggers allergic activation?

re-exposure to allergen cross-links IgE on mast cells, leading to degranulation and mediator release

What are the immediate effects of mast cell activation?

release of histamine and lipid mediators causing vasodilation, vascular permeability, and smooth muscle contraction

What is the late-phase allergic reaction?

infiltration of inflammatory cells (eosinophils, neutrophils) hours after initial activation

What are common environmental contributors to allergy?

hygiene hypothesis, infections, tobacco smoke, vitamin D deficiency, obesity, dietary fats

How is allergy treated?

avoidance, antihistamines, allergen immunotherapy, and monoclonal antibodies (e.g., anti-IL-4) for severe cases

How does the immune system recognise tumours?

by detecting tumor antigens, including mutated proteins, viral antigens, overexpressed proteins, and cancer germline antigens

What are tumour antigens?

proteins expressed by tumor cells that can be targeted by the immune system; may be unique (mutated) or shared (overexpressed)

What is immunoediting?

he process by which the immune system shapes tumour evolution through Elimination, Equilibrium, and Escape

What happens in the Elimination phase of immunoediting?

innate and adaptive immune cells recognise and destroy highly immunogenic tumor cells

What is the Equilibrium phase of immunoediting?

immune system controls tumour growth but does not fully eliminate it, leading to selection of less immunogenic variants

What is the Escape phase of immunoediting?

tumour variants avoid immune detection or suppression and grow unchecked

What are mechanisms of tumour immune evasion?

antigen loss, downregulation of MHC I, secretion of immunosuppressive cytokines (e.g., TGF-β), expression of checkpoint ligands (e.g., PD-L1)

Which immune cells contribute to tumour evasion?

Regulatory T cells (Tregs), tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells

How does tumour metabolism affect immunity?

tumour cells outcompete T cells for glucose, impairing T cell function

What is cancer immunotherapy?

treatment that harnesses or enhances the immune system's ability to fight cancer

What are adaptive cell therapies?

transfer of tumour-specific T cells (natural or engineered) expanded ex vivo into patients

What are therapeutic monoclonal antibodies?

Lab-produced antibodies that target tumour antigens or deplete tumour cells (e.g., Rituximab)

What are immune checkpoints?

Regulatory pathways (e.g., CTLA-4, PD-1) that limit T cell activation and prevent excessive responses

How do checkpoint inhibitors work?

By blocking CTLA-4 or PD-1/PD-L1, they release the "brakes" on T cells, restoring anti-tumour activity

What is the function of CTLA-4?

competes with CD28 to block co-stimulation during T cell priming in lymph nodes

What is the function of PD-1?

binds PD-L1/PD-L2 in tissues, inhibiting TCR signalling and reducing T cell function

Why do tumors express PD-L1?

to suppress T cell activity and evade immune detection

How do immune checkpoint inhibitors impact cancer therapy?

they can significantly improve T cell-mediated tumour control and survival in several cancers