Immunology exam 4

What is immunization?

Process by which an individual becomes protected against particular diseases through passive or active immunity. Individual biomes immune to a specific infection/ disease through vaccination.

What is passive immunity?

Already made antibodies are given to a patient. Does not give long term protection but is used for immediate protection (no memory). Can be done as natural passive immunity by transferring IgG through passive immunity from the placenta or IgA breastmilk to offspring. Can also be artificial passive immunity  by pooling antibodies from donors which can have a wide range of antibodies. Such as antitoxins/ antivenoms and antibody therapies.

What is active immunity?

Occurs when exposed to an antigen and the body generates its own immune response and generates memory cells. This can have a slower and more sustained immune response. Natural would be getting infected by the pathogen and building immune cell and artificial would be the use of vaccines to build immunity.

What is vaccination?

Deliberate exposure of pathogen antigens to the body in order to generate protective immunity and immunological memory without causing disease.

Primary immune response?

Occurs when an antigen is first encountered in the body. Slow and generates plasma cells to produce antibodies, activates naive T and B cells, and establishes memory B and T cells.

Secondary immune response?

Occurs when the same antigen is encountered again generating a faster response. Memory cells respond quickly and antibody production increases quickly/ have higher affinity for antigen.

What are the steps to vaccine design? 

1. Antigen needs to be accessible to the immune system.

2. Pathogen needs to survive in system without mutating

3. Needs to be stable and conserved across strains for broad protection

4. Antigen must stimulate B and T cell response for broad immunity

5. Antigen must have low similarity to human proteins to reduce risk of self reactivity

What are adjuvants?

Substance added to vaccine to enhance immune response. It cna prolong antigen presence inducing local inflammation and co-stimulates and stimulates lymphocyte proliferation.

What are common adjuvants? 

1. Alum- slows antigen release/ increases phagocytosis

2. TLR agonists mimics bacterial/ viral components to activate innate immunity

What are Live Attenuated Vaccines?

They contain weakened forms of a “wild” pathogen that can replicate to a limited extent in the host and target immune system directly to trigger immune response. Can mimic natural infection and can be presented by MHC molecules to CD4 and Cd8 T cells. Risks include virulence and disease to immunocompromised patients.

What are inactivated vaccines?

 Contain pathogens that have been killed by chemical/ physical treatment. They do not replicate in the host but still generate a weaker immune response. Due to lack of antigen replication in the body it can not be presented by MHC molecules to CD4 and CD8 T cells. Known as boosters and adjuvants can be added.

What are subunit vaccines (recombinant, polysaccharide,and conjugate vaccines)?

Have purified components of pathogen rather than the whole pathogen. This does not cause CD4 and CD8 T cell to respond and induces protective immune responses. Pathogen components used in vaccines are protein and polysaccharides.

What are polysaccharide vaccines?

Pathogenic bacteria are surrounded by polysaccharide capsules that help them evade immune recognition and resist phagocytosis and because the capsule is exposed on the bacterial surface, it can serve as a useful vaccine target. When antibodies are generated they bind to the bacterial surface and promote opsonization. Induces strong B cell and weak T cell responses

What are Conjugate vaccines?

chemically links polysaccharide antigens to a carrier protein/ to be processed and presented to helper T cells. This can increase immune and antibody production/ class switching, maturation, and long-term memory.

What are recombinant protein vaccines?

Contain purified antigen proteins made by using recombinant DNA technology. The vaccine can not replicate and cause infection.  This results in weaker immune activation and often requires adjuvants in multiple doses to generate a strong response.

What are mRNA vaccines?

Made up of a small insoluble portion of a viruses genetic material to carry the gene to the host cells to be encoded. The host cell translates the viral RNA into the antigen protein which is then processed and presented to MHCs to initiate an immune response. This causes B and CD8T cells to respond.

What vaccine produces the antigen inside of the host cell for immune response?

mRNA vaccines activating antibody and CD8+ T cell responses.

What is a viral vector vaccine?

Made of a small portion of engineered viral genetic material with a viral capsule that encodes this to host cells. This infects the host cells and the viral gene is expressed to produce the antigen protein. The antigen is then processed and presented on MHCs to stimulate adaptive immune responses involving antibodies and T cells.

What are challenges in vaccine development?

Antigenic variation, complex life cycles, immune evasion strategies and intracellular persistence.

What is antigenic variation?

Some pathogens frequently change their surface antigens, allowing them to escape previously generated immune responses (e.g., influenza, HIV).

What are pathogenic complex life cycles that contribute to vaccine challenges?

Pathogens such as parasites express different antigens at different stages, making it difficult to target them with a single vaccine.

What is pathogenic immune invasion?

Many pathogens actively interfere with immune detection or suppress immune responses.

What is intracellular persistence and how does it challenge vaccine development?

Some pathogens hide inside host cells, where antibodies are less effective and protection may require strong T-cell responses.

What are vaccine boosters?

 Given normally as a second vaccine after the main first vaccine to increase protection after the first vaccination declines over time or viral variation. This is to increase circulating antibodies by re-exposing the immune system to the antigen to trigger a stronger secondary immune response. 

How does population size affect vaccination?

The larger population that is vaccinated decreases the likelihood of someone in the population getting the virus and causes heard immunity which protects immunocompromised patients, and infants

Emerging vaccine strategies? 

• Wildlife vaccination strategies  – novel methods to immunize animal populations (e.g., mosquitoes engineered to inoculate bats against rabies).

•  Self-spreading vaccines – vaccines designed to transmit between animals to rapidly immunize wildlife populations.

•  Transmission-blocking vaccines – vaccines that prevent pathogens from spreading to new hosts (e.g., malaria transmission blocking).

• Therapeutic vaccines – vaccines designed to treat diseases such as cancer or addiction.

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What is the best cell to activate naive CD4?

Dendritic cells

How does antigenic variation reduce vaccine effectiveness?

It alters epitopes and affects the binding of previously generated antibodies

What is hypersensitivity?

An exaggerated response to an antigen from antibody or cell mediated immune mechanisms which can lead to injury. This is separated into 4 types.

What is type 1 hypersensitivity?

When allergen is bound to IgE receptors cross-link triggering cell activation/ degranulation when IgE binds to Fc receptors on mast cells, basophils, and eosinophils causing wheezing, hives, and runny nose.

What are the phases of the type 1 hypersensitivity response?

Sensitization phase, effector phase, and late phase

What is the sensitization phase?

Occurs when the immune system first encounters the allergen.

What is the effector phase?

(Occurs within minutes) when re-exposed to the allergen it binds/ cross-links two or more IgE molecules on mast cells. This triggers a signal cascade causing degranulation/ pre-formed mediators and newly synthesized lipid mediators that act together to produce redness, swelling, itching, and mucous production.

What is the late phase?

(Occurs within hours) The signal in the effector phase is sustained by cytokines released from mast cells and Th2 cells. This recruits eosinophils, basophils and more Th2 cells causing more inflammation and tissue damage. This can cause asthma, eczema and airway obstruction.

What are key cells involved in type 1 hypersensitivity? 

• Mast Cells − Primary effector cells of Type I hypersensitivity. Activated by allergens and undergoing degranulation. 

• B cells and Plasma cells − Produce IgE after class switching under Th2 cytokines.  The secreted IgE binds to FcεRI on mast cells, basophils, and eosinophils, priming them for activation.

•  Basophils − Circulating counterparts of mast cells with similar mediator release. Contribute to systemic allergic responses and anaphylaxis. 

• Eosinophils − Recruited during late-phase allergic inflammation. Release toxic proteins and lipid mediators that amplify tissue damage and inflammation. 

• Th2 Cells − Provide the cytokines needed for IgE production and eosinophil recruitment.

What are allergic reaction mediators? 

Chemical mediators released by mast cells via histamine, leukotrienes/prostaglandins, and cytokines/ chemokines

Histamine

released within minutes; causes itching, swelling, mucus secretion, and smooth muscle contraction. 

Leukotrienes & Prostaglandins

 formed after activation; prolong inflammation, cause bronchoconstriction, and increase vascular leakiness (major role in asthma). 

Cytokines & Chemokines

released later; recruit more immune cells and sustain inflammation (e.g., IL-4, IL-5, IL-13, TNF-α)

What is the atopic march?

When childhood eczema can progress to asthma and food allergies.

What is systemic anaphylaxis (type I)?

Most severe/ life threatening allergic reaction occurring in minutes if untreated. When allergens enter the bloodstream causing widespread mast cell degranulation triggering airway obstruction, low bp, and swelling due to edema.

What is allergic rhinitis (hay fever Type)?

Common atopic airway disorder caused when allergens are inhaled and usually inherited. This causes itching, sneezing, watery/ itchy eye and asthma. 

How do food allergies occur (type I response)?

First occurring through the skin epithelial cells release signals activating dendritic cells and Th2 cells promoting IgE production by B cells. These then travel to the gut and attach to mast cells. When re-exposed to the allergen the mast cells release mediators such as histamine, leukotrienes, and cytokines causing allergy symptoms.

What are allergens?

Normally harmless antigens that can be tolerated or ignored but could trigger larger responses en mass. exp) nuts, soy, pollen, ragweed, animal dander, venom, penicillin

What causes allergies?

When the immune system fails to maintain tolerance to harmless antigens and mounts a Th2-driven, IgE-mediated response. The antigen favors Th2 differentiation due to  Antigen-presenting cells activate naïve CD4⁺ T cells & These differentiate into Th2 cells rather than regulatory T cells (Tregs). This can also be due to barrier disruptions due to the antigen triggering this response.

Do genetics play a role in allergies?

Yes, they tend to run in families such as inherited skin/mucosal integrity, immune signalling balance, and mast cell sensitivity.

How do environmental factors affect allergy sensitivity?

Due to environmental exposure such as air pollution, low microbial exposure, and diet which can contribute to immune hypersensitivity triggering immune responses.

How is type 1 hypersensitivity generally diagnosed?

This can be done through allergy tests such as ELISA blood test, when small allergens are pushed under the skin to see if there is a response, to see if IgE binds to the allergen-coated surface.

How is type I hypersensitivity generally treated?

With antihistamines, decongestants, corticosteroids, epinephrine, and anti-IgE antibody which prevents IgE from binding tto mast cells inhibiting severe allergic responses.

What is desensitization or immunotherapy?

This is the gradual exposure to small doses of allergen to reduce sensitivity over time. This could cause the immune system to build up tolerance rather than favor Th2 responses. This promotes the production of IgG instead of IgE.

What is Atopy?

The genetic predisposition to developing IgE-mediated Type 1 hypersensitivity responses to harmless antigens that occur when normal barrier/ immune responses are altered in a way that favors IgE responses.

What contributes to Atopy? 

1. Weak barrier function allowing allergens in more easily

2. Immune signalling(Th2 bias)- leading to IgE instead of tolerance such as signalling IL-4/ IL-3

3. Sensitivity in Effector responses triggering mast cells and eosinophils to response strongly 

What is type 2 Hypersensitivity?

Result of IgG/ IgM antibodies binding to cell surface antigens which recognize the antibody fc receptor killing the cell with the antibody bound to it.

What are the major mechanisms of type 2 hypersensitivity?

complement -mediated cytotoxicity, antibody mediated cytotoxicity, and antibody mediated cellular dysfunction.

Complement-mediated cytotoxicity:

Antibodies activate complement proteins/ promote opsonization for phagocytosis. 

Antibody-dependent cell-mediated cytotoxicity:

NK cells recognize antibody-coated cells and release cytotoxic molecules to induce cell death.

Antibody-mediated cellular dysfunction:

Antibodies bind to functional receptors, either blocking or overstimulating them, altering normal cell activity

What are transfusion reactions (type II reaction)?

When a person receives blood containing non-self ABO antigens, the body creates antibodies against the blood antigens they lack such as type A producing anti-B IgM that binds to type B donor rBCs. This activated compliments causing intravascular hemolysis and release of hemoglobin causing fever, chills, low bp, back pain, and kidney damage.

What is newborn hemolytic disease (type II reaction)?

When the mother is Rh- and the fetus is Rh+ resulting in the mother forming anti Rh IgG which crosses the placenta and destroys fetal Rh + RBCs causing anemia, jaundice, and elevated newborn bilirubin. This can be prevented by giving the mother anti-Rh IgG.

T/F is graves disease and goodpasture syndrome a type II reaction?

TRUE

What is immune complex-mediated Type III hypersensitivity?

Caused by excess antigen-antibody complexes that are not cleared efficiently and could deposit in tissues. This causes local inflammation and activates immune pathways to release enzymes/ inflammatory mediators that can damage tissues. This can be via exogenous antigens such as bacteria/ viruses or endogenous antigens such as self components and autoimmune issues. Involves mainly IgG and something IgM.

What is Arthus reaction (type III response)?

Localized inflammation is when antigen is injected into tissues of someone who has antibody activating complement and recruiting immune cells causing redness, swelling, inflammation, and bleeding within 4-10 hrs. exp) insect bites/ allergen inhalation

What is serum sickness (type III response)?

When a person is exposed to foreign serum proteins (antitoxins/ antivenoms in horses) the serum acts as a foreign antigen triggering antibody production and the antibody-antigen complexes form in circulation causing a reaction in 7-10 days a triggering rash, fever, joint pain, swollen lymph nodes, and kidney inflammation?

What is delayed type IV hypersensitivity?

This involves T cells NOT antibodies. This is driven by Th1 cells and some CD8+ cytotoxic T cells. Reaction generally occurs within 24-72 hours after exposure causing swelling, redness. 

What can trigger type IV responses?

• Haptens -  Nickel, latex, urushiol (poison ivy/oak), cosmetics, hair dye (paraphenylenediamine), topical antibiotics (e.g., neomycin), penicillin. 

•  Complete antigens (microbial or protein antigens) - such as Mycobacterium tuberculosis (tuberculin test), viral antigens, certain graft antigens.

What is the sensitization phase of type IV response?

When first exposed to the antigen, dendritic cells or macrophages process the antigen and present it on mHC II to naive CD4+ T cells. IL-12 from APC,drives differentiation of T cells into Th1 effector cells. WHen activated these cells proliferate to form memory cells for future rapid response. This takes 1-2 weeks.

What is the effector phase of Type IV response?

Occurs when re-exposed to the same antigen and memory Th1 cells recognize antigen presented on MHCII presented by APCs. The activated Th1 cells secrete cytokines to recruit and activate macrophages to kill activity and reduce inflammation at the infection site.

What is contact dermatitis (type IV response)?

Sensitization occurs when skin proteins become in contact with chemical hapten. The modified proteins are presented to T cells and can be caused by poison ivy, medication, cosmetics, metal ions, or chemicals and can cause blister-like lesions on the skin.

How can nickel cause contact dermatitis?

 It binds to skin proteins and activates Th1/ Th17 responses causing rashes when in contact with the skin.

How can poison ivy cause contact dermatitis?

 Urushiol, a type of poison ivy resin, binds to skin proteins after being oxidized to activate th1/th17 cells causing blisters on the skin.

How does type IV hypersensitivity help control tuberculosis?

Due to antibodies being ineffective against bacteria in macrophages, persistent exposure to the antigen causes continuous Th1 activation/ cytokine release to keep macrophages active. The activated macrophages enlarge/ fuse to form multinucleated cells surrounded by Th1 cells called granulomas that prevent the spread of the pathogen!

What is DTH testing and how is it used?

This is used to test T cell memory to test if the cells have been previously exposed to an antigen or not. This is done  by injecting a purified protein derivative intradermally and waiting to see if a red firm bump appears within 48-72 hours to determine if Th1 cells have released cytokines to recruit macrophages. This would then confirm the previous exposure to the antigen and T cell memory cell presence. 

What is immune tolerance?

When the immune system remains unresponsive to self-antigens preventing tissue damage through central tolerance and peripheral tolerance to prevent autoimmunity.

What is central tolerance?

During lymphocyte development in the bone marrow/ thymus to eliminate self reactive cells

What is peripheral tolerance?

Occurs after lymphocytes mature as a backup mechanism to prevent activation of self antigens and harmless envr antigens at barrier sites to prevent inflammation

How is tolerance used to prevent activation to harmless foreign antigens?

When  barrier sites encounter harmless antigens, these sites recruit regulatory mechanisms that favor non inflammation/ tolerogenic responses to suppress activation when these antigens are sampled by immune cells.

How is tolerance displayed in the gut?

The GI tract has the most diverse population of immune cells  in the body. When exposed to antigens the immune cells need to be able to discern threats from harmless antigens. This is done using cues from epithelial cells, microbiota, and local cytokines to identify them. This can be done using the physical barrier, chemical barrier, biological barrier, and immune barrier.

What is the role of the physical barrier in the gut?

 a single epithelial layer linked by tight junctions that limits microbial entry

What is the role of the chemical barrier in the gut?

mucus and antimicrobial peptides

secreted by epithelial cells and Paneth cells.

What is the role of the biological barrier in the gut?

commensal microbes that outcompete pathogens and produce metabolites influencing host immunity.

What is the role of the immune barrier in the gut?

intraepithelial lymphocytes (IELs), dendritic cells, Tregs, and IgA-secreting plasma cells in the lamina propria that sustain tolerance andprotection simultaneously.

What is the role of the innate immune system in the gut?

This is done through the use of:

• Epithelial cells- detect signals via PAMPs/ release regulatory cytokines to control inflammation and induce local tolerance

• Macrophages- clear apoptotic cells silently produce IL10 reducing inflammation

• Dendritic cells- samples luminal antigens/ migrate to mesenteric lymph nodes to present low costimulatory antigen to promote Treg induction, IgA class switching

• Innate lymphoid cells (ILC3’s)- maintains epithelial integrity, barrier repair, and limits microbial translocation

What is the role of the adaptive immune system in the gut?

This is done through the use of:

• IELs- ignore harmless antigens by being in a non-inflammatory regulated form

• Tregs- secretes IL-10 and TGF-B to suppress excessive responses/ supports IgA production

• B cells- produces IgA to coat microbes/ food antigens to inhibit contact with epithelium/ avoiding inflammation

• Th17- produces IL-22 for epithelial maintenance/repair &  antimicrobial peptide release

What is the role of microbiota in the gut?

This is essential in maintaining peripheral tolerance! This shapes early immune development and drives epithelial maturation. This prevents microbial expansion and reduces inflammation.

How does clostridia and bacteroides aid in gut tolerance?

species promote Treg differentiation through microbial metabolites such as short-chain fatty acids (SCFAs), notably butyrate, acetate, and propionate.

How do SCFAS from microbiota aid in gut tolerance?

strengthen epithelial tight junctions, enhance mucus production, and inhibit pro- inflammatory pathways like NF-κB.

What is immune dysregulation in IBD?

Immune mediation can cause Crohn's disease and ulcerative colitis when tolerance is not maintained. This is due to bacterial contact with the gut mucosa activating DCs, macrophages, and effector T cell pathways causing inflammation. This prolonged inflammation causes ulcers, chronic mucosal injuries, and impaired healing producing extraintestinal inflammatory disease. 

What are common autoimmune disorders?

type I diabetes, rheumatoid arthritis, multiple sclerosis, celiac disease, hashimoto’s thyroiditis, graves’ disease, lupus, psoriatic arthritis, and addison’s disease.

What are risk factors that play into autoimmunity?

Genetics, environmental factors, defects in self- reactive B and T cells, and overlapping factors

How do genetic factors play into autoimmunity?

Can be influenced by genes that regulate antigen presentation, inflammation and tolerance. Variants in immune signalling pathways, HLA alleles affecting susceptibility to self antigens and gene mutations can affect improper signalling as well.

What are some genetic mutations that affect autoimmunity?

AIRE & FOXP3 mutations which impair central/ peripheral tolerance and can affect many other genes. This would impair regulation of autoreactive cells.

How do infections cause autoimmunity?

This can increase costimulation/ cytokine production activating autoreactive lymphocytes. This causes Molecular mimicry when the microbial antigens mimic self antigens causing cross reactivity! This can trigger/ amplify inflammation.

What are some examples of infections that cause autoimmunity?

Guillain Barre, Epstein Barre, Rheumatic heart disease, 

How does barrier dysfunction cause autoimmunity?

This is the disruptions in the tight junctions in immune barriers which allow microbes into tissues/ circulation. This can lead to chronic inflammation and innate activation which can lead to barrier breakdown. This can weaken mechanisms promoting decreased peripheral tolerance and increase likelihood of activating self-reactive lymphocytes contributing to autoimmunity!

What are examples of autoimmunity caused by barrier dysfunction?

Rheumatoid arthritis, type 1 diabetes, and lupus.

What is the immunology behind rheumatoid arthritis?

Chronic systemic infection causing inflammation activating cytokine and other immune cells. B cells contribute autoantibodies while other immune cells amplify the inflammation causing tissues destructive pathways and cartilage damage. 

What is the immunology behind Type 1 diabetes?

This is barrier dysfunction causing autoimmunity where the body does not produce sufficient insulin due to loss of B cells causing glucose to not get into the cells so the individual has to administer insulin to the body. 

What is the immunology behind systemic lupus?

 Barrier disruption causing autoimmunity when dead cells are not cleared effectively in the body activating B and T cells and causes self- antigens to be attacked by autoantibodies leading to rashes and inflammation

What are some broad spectrum autoimmunity treatments?

1.Corticosteroids and immunosuppressants: inhibit cytokine production, lymphocyte

2.Cytotoxic and anti-inflammatory agents: broadly suppress immune cell activity; effective but nonspecific. 

3. Disease-specific supportive therapy: treatments that manage the consequences of tissue damage rather than the autoimmunity itself (e.g., insulin for type 1 diabetes, antithyroid medications for Graves’ disease). 

What are the two types of targeted cell therapies?

− B-cell depletion: monoclonal antibody to CD20 (rituximab) reduces antibody-producing cells (e.g. lupus).

 − T-cell modulation: agents targeting CTLA-4 (abatacept) block costimulation to dampen T-cell