Immunology Test 4

Vaccine

• deliberate delivery of pathogen antigens that can elicit a primary immune response but have little or no pathogenic potential

• goal is development of long-lasting immunological memory

Small pox Vaccine

first medically prescribed vaccine; resulted in global eradication in 1979

Live-attenuated pathogen

has been produced, to date, by growing in cells from another species

• becomes less able to grow in human cells, and therefore less pathogenic

• typically elicit the strongest memory responses

Killed/inactivated pathogens

are unable to replicate and cause infection

• typically generate a weaker memory response than live-attenuated vaccines because they don’t as effectively mimic a natural infection (but the memory response is still effective)

Subunit Vaccines

• do not contain whole cells; contain only antigens that best stimulate the immune system

• may need to contain an adjuvant

  • a substance that stimulates the innate immune system

  • because the vaccine alone may not contain PAMPs to activate an innate immune response and activate dendritic cells

Examples of Subunit Vaccines

• e.g., Hepatitis B vaccine delivers only the HBV surface antigen

• e.g., Tetanus, Diphtheria acellular Pertussis vaccine (TDaP) delivers the purified tetanus and diphtheria toxoids and B. Pertussis antigens

• e.g., Human papillomavirus vaccine (HPV) delivers viral capsid proteins

• Novavax COVID-19 vaccines delivers antigens from the spike protein

Bacterial capsular polysaccharides

are conjugated to a protein to produce a T-cell dependent response in infants

• necessary because infants elicit weak T-cell independent responses to thymus independent type 2 (TI-2) antigens such as repetitive carbohydrate structures

• e.g., H. influenzae vaccine

• e.g., N. menengitidis vaccine

mRNA vaccines for COVID-19 (Pfizer and Moderna)

• deliver mRNA encoding the spike protein from the COVID-19 virus

• in the body, the mRNA is translated into the COVID-19 spike protein, and an immune response is generated against the spike protein

• like a subunit vaccine, only using mRNA encoding the subunit

Viral vector vaccine for COVID-19 (Johnson&Johnson)

• uses a different virus (a non-pathogenic virus that does not cause disease) to infect cells and deliver DNA encoding the spike protein from the COVID-19 virus

• an immune response is generated against the spike protein

• like a subunit vaccine only using a viral vector to deliver DNA encoding the subunit

Herd Immunity

a large majority of immune individuals protect a small minority of non-immune individuals

• smaller probability that non-immune individuals will encounter the pathogen

• chains of infection are disrupted

• decreased vaccination rates cause a loss of this

Hypersensitivity/allergic reaction

an adaptive immune response to non-microbial environmental antigens

Allergen

an antigen that causes a hypersensitivity/allergic reaction

In less developed countries

where helminth (worms) infections are common, IgE responses protect against helminth infection

• allergies have a lower prevalence

In more developed countries

where helminth infections are rare, IgE responses are more often responsible for type I hypersensitivity reactions

• allergies have a higher prevalence

• also called immediate hypersensitivity reactions

Activation of type I hypersensitivity reaction

• mast cells are in tissues underlying body surfaces and surrounding blood vessels

• primary exposure to an allergen results differentiation of TH2 and class switching to IgE

• IgE binds to mast cells and sensitizes the mast cell to the allergen

• next time the allergen enters the tissue, it binds to IgE and causes mast cell degranulation

  • type I hypersensitivity reaction is also referred to as an immediate hypersensitivity reaction because the effects of mast cell degranulation are immediate

Mast Cell Activation

• IgE binds to Fcε receptors on mast cells and sensitizes the mast cell to the antigen recognized by the IgE

  • mast cells are long lived so a single mast cell can accrue multiple IgE antibodies and become sensitized to multiple antigens

• when an IgE antibody binds its antigen, the mast cell degranulates

• molecules released by mast cells act to:

  • physically expel the pathogen

  • recruit other leukocytes

Eosinophils

• resident in connective tissues underlying body surfaces

• numbers are low in the absence of infection and only express Fcε when activated

Eosinophil Functions

• release cytotoxic molecules to damage pathogen

• amplify the mast cell inflammatory response

An immediate reaction

• due to immediate release of mast cell pre-packaged granules

• for intradermal allergen: Edema and reddening of skin result in wheal and flare reaction

• Edema and constriction of smooth muscle result in airway narrowing

A late-phase reaction

• caused by molecules synthesized within several hours of mast cell activation

• a late phase response occurs in ~50% of individuals in these controlled studies

• intradermal allergen: increased area of edema

• inhaled allergen: second phase of airway narrowing

Reduced exposure to microbial antigens in early childhood

the main environmental factor implicated in increased prevalence of allergies in recent decades

• this is known as the “hygiene hypothesis”

• less early exposure to common microbial antigens may affect early “training” of the immune system as the maturing immune system gets less “practice”; a poorly educated immune system is more likely to respond appropriately to non-microbial antigens

Genetic and environmental factors

both contribute to the development of allergies

The symptoms of type I hypersensitivities

are all caused by the same mechanism (i.e., allergen binding to IgE on mast cells), but symptoms vary depending on the location of the mast cell

Molecules released from mast cells

• act on blood vessels to increase blood vessel permeability, which causes fluid to move out of blood vessels and into the tissue

• act on smooth muscle to cause smooth muscle contraction

• cause increased mucus production

Allergic rhinitis (hay fever)

• allergen enters through the nasal mucosa and activates mast cells in underlying tissues

• causes local edema, blocked nasal passages, increased mucus production

Allergic conjunctivitis

• allergen enters through the conjunctiva

• causes watery inflamed eyes

Asthma

• allergen enters through the lower respiratory tract mucosa and activates mast cells in underlying tissue

• can have an acute response and a chronic response

Acute response

causes bronchial constriction (narrowing of the airways) due to smooth muscle contraction, increased mucus, and swelling (due to increased blood vessel permeability)

Chronic response

• caused by continued presence of TH2 cells, eosinophils and other leukocytes

• causes persistent airway tissue remodeling which permanently narrows the airways (due to increase in the size and number of smooth muscle cells)

• becomes a type IV hypersensitivity

Urticaria (hives) and angioedema

• caused by allergens in tissue underlying skin

• allergen activates mast cells underlying the skin surface

• caused raised swellings due to increased permeability of blood vessels

• urticaria (hives): swelling at the surface of the skin

• angioedema: swelling in deeper layers of the skin

Systemic anaphylaxis

• caused by allergens entering the blood stream

• allergens can be injected directly into the blood via insect/animal bites

• allergens can be absorbed into the blood stream (e.g., food and drug allergens)

• allergens bind to mast cells in connective tissues around the body that surrounds blood vessels

Symptoms of Systemic anaphylaxis

• can be mild, such as hives

  • allergen leaves the blood and enters the skin, causing a disseminated wheal and flare reaction

• can be serious, even fatal, resulting in anaphylactic shock

  • allergen activates mast cells surrounding blood vessels all over the body, causing loss of blood pressure (due to fluid moving out of blood vessels into tissue)

  • constriction of airways and swelling of epiglottis can lead to asphyxiation

Food allergens

can stay in the gut only and activate mast cells in the local gut mucosal tissues

• causes cramps, vomiting and diarrhea

Epinephrine

used to prevent anaphylactic shock

• stimulates reformation of tight junctions and relaxation of smooth muscle

Anti-histamines

relieve symptoms of rhino-conjuctivitis and urticaria

• block histamine receptor

Corticosteroids

promote dilation of bronchial smooth muscle

Monoclonal anti-IgE antibody (omalizumab)

• prevents IgE binding to IgE receptors

• used to control chronic asthma

Type II hypersensitivity

• an allergen modifies a host cell surface antigen making it into a foreign antigen not normally present in the body

• an IgM/IgG antibody response is directed at the modified cell surface antigen

  • IgG tags the host cells for opsonization and activates the complement system and ADCC

• e.g., penicillin and similar drug derivatives with a β-lactam ring

Type III hypersensitivity

• the allergen is an excess of small soluble antigen that forms antigen:antigen immune complexes

• Immune responses are carried out by antibodies in the complexes

  • the immune complexes deposit in blood capillaries, lung alveoli, and glomeruli of kidney and trigger activation of the classical complement pathway and recruitment of phagocytes, which cause damage to vessels.

Type IV hypersensitivity

• immune response is due to actions of effector T-cells

• often caused by direct skin contact with an allergen

  • allergen penetrates the skin and is taken up by antigen presenting cells

  • can cause activation of CD4 T-cells or CD8 T-cells, depending on the antigen

  • e.g., urushiol oil in poison ivy, nickel, some insect bites, chronic asthma

• also called delayed hypersensitivity reactions

  • symptoms occur within 24-48 hours, but are not immediate like the type I response

  • symptoms are caused by a T-cell memory response to the allergen

Histocompatibility

donor and recipient have compatible surface antigens

Alloantigens

antigens that differ between members of the same species

• ex. MHC molecules, ABO antigens

Alloreaction

an immune response against alloantigens

• are the major impediment to successful transplantation

• are “foreign” to the body

Autograft

transplantation of a tissue from one site to another on the same individual

• can be performed with 100% success; perfect histocompatibility

Isograft

transplant between identical twins

• can be performed with 100% success; (near) perfect histocompatibility

Allograft

transplant between genetically different individuals

• never perfect histocompatibility

• adaptive immune responses are made to alloantigens in the transplanted tissue

Blood Transfusions

• blood is the most commonly transplanted tissue

• donor and recipient must be matched for the ABO and Rhesus D (RhD) antigens

  • MHC matching is not necessary for blood transfusions

  • blood cells contain other surface alloantigens that are not as highly immunogenic as the ABO and Rh antigens and are therefore not routinely typed

Solid Organ Transplantations

an immune response to alloantigens contributes greatly to loss of function of solid organ transplants

• the major alloantigens that cause rejection of solid organ transplants are MHC molecules

• a high level of MHC histocompatibility is often not possible for solid organ transplants

• advances in immunosuppression have transplant success rates

• over half of kidney transplants still fail by 10 years

Solid organ transplantations: hyperacute rejection

caused by existing antibodies that react with alloantigens on blood vessels of the grafted tissue (inc. ABO antigens and MHC antigens)

• existing antibodies can arise from pregnancy, blood transfusions or previous transplants

• reaction occurs within 24 hours of transplantation

• vessels become blocked and damaged, leading to death of the transplanted tissue

can be avoided by blood typing and performing a cross match prior to transplantation

• a patient’s blood serum is tested to see if there are antibodies that react to donor blood cells

Solid Organ transplantation: acute rejection

caused by activation of T-cells by alloantigens in the grafted tissue

• transplants are monitored for symptoms of acute rejection and treated with immunosuppression

• a major risk factor for chronic rejection

Indirect Recognition

• recipient dendritic cells infiltrate the grafted tissue and present self MHC: alloantigen complexes to recipient T-cells (alloantigens include peptides from donor MHC molecules present in the graft)

• recipient T-cells are activated by alloantigens

• recipient T-cells then activate recipient macrophages and recipient B-cells displaying the same peptide:MHC complex

Direct Recognition

• donor dendritic cells present in the grafted tissue present donor MHC:peptide complexes to recipient T-cells

• a significant number of recipient T-cell receptors can bind donor MHC molecules (contrary to MHC restriction). the T-cells become activated as they have not been negatively selected against donor MHC complexes

• recipient T-cells respond to donor cells displaying the same donor MHC:peptide complex (CD4 T-cells will activate donor macrophages and CD8 T-cells will destroy cells in the grafted tissue)

Minor histocompatibility antigens

• alloantigens of non-MHC proteins

  • even a graft from an MHC identical sibling will show histo-incompatibility of other alloantigens

  • an immune response will be produced to minor alloantigens, but it will develop slower than the immune response to the major alloantigens

Hematopoietic stem cell transplantation (HSCT)

• the recipient’s bone marrow is destroyed to:

  • reduce the number of recipient hematopoietic stem cells, immunosuppressed the recipient, reduce the number of tumor cells (if cancer)

  • protocol also damages dividing host cells (particularly skin, gut, liver)

• donor hematopoietic stem cells are infused and repopulate the recipient’s bone marrow (engraftment)

  • recipient produces blood cells of donor origin

HSCT

is most commonly performed to treat cancers and other disorder of red blood cells and white blood cells (immune system cells)

• blood cells from the patient are replaced with blood cells from a donor

Graft-versus-host disease (GVHD)

can occur following hematopoietic stem cell transplantation

• it is caused by donor T-cells attacking recipient tissues

  • MHC molecules are the major alloantigens that stimulate GVHD

    • recipient and donor dendritic cells can both play a role in donor T-cell activation (in mechanisms analogous to what we looked at for acute allograft rejection)

  • acute GVHD primarily affects the skin, gut and liver which are inflamed following the irradiation and chemotherapy protocol prior to transplantation

• donor T-cells promote engraftment of HSCs and reconstitute the recipient’s immune system.

  • immune reconstitution is suppressed without donor T-cells

Autoimmune response

an immune response against self-antigens

Autoantigens

self-antigens that trigger an immune response

Negative Selection

• selects against lymphocytes that are strongly/moderately “self-reactive”

• many lymphocytes weakly reactive to “self-antigens” will escape

  • many lymphocytes that are weakly self-reactive can also recognize foreign antigens

  • if all weakly self-reactive lymphocytes were eliminated, the immune response would be impaired

  • however, weakly self-reactive lymphocytes can potentially produce an autoimmune disease

Lymphocyte requirement for co-stimulation

• T-cells are activated when their receptor binds antigen in the presence of a co-stimulatory signal from the dendritic cell

• B-cell activation requires signals delivered from a conjugate Tfh cells, which must recognize a linked antigen

• lymphocytes that bind antigen in the absence of co-stimulation are signaled to undergo apoptosis or become anergic

Tregs

• some T-cells that are negatively selected during development in the thymus become Tregs (natural Tregs)

• Naïve T-cells that bind antigen in the presence of anti-inflammatory cytokines become these

• can inhibit activation of other T cells that recognize autoantigen being presented by the same cell

  • do not have to recognize the same antigens

The breaking of self-tolerance

dendritic cells could pick up self-antigens in the presence of and infection and become activated (mature) by microbial PAMPs taken up at the same time. The dendritic cell could then activate self-reactive T-cells.

• inflammatory cytokines produced during an infection may also down-regulate Treg responses

Autoimmune disorders

• responses resemble those that target invading pathogens, but the autoantigens often cannot be removed

  • chronic

• usually arise spontaneously

  • autoantigens are well characterized, but what triggers the initial immune response against them is not

• immune mechanisms are analogous to type II, III, and IV hypersensitivity reactions

Autoimmune hemolytic anemia

• IgG antibodies are directed at an antigen on RBCs

• results in opsonization, activation of complement system and ADCC

Grave’s disease

antibodies directed at thyroid receptor stimulate excessive production of thyroid hormone, results in hyperthyroid

Myasthenia gravis

antibodies directed at acetylcholine receptor at neuromuscular junction blocks nerve transmission, results in weakness and rapid fatigue

Systemic lupus erythematosus

• autoantigens are ubiquitous cellular antigens released at high concentration from apoptotic cells or damaged tissue

• form small antigen:antibody immune complexes that deposit glomeruli of kidney, joints, and blood vessels of the skin and other organs causing inflammation and damage via activation of classical complement pathway

Multiple sclerosis

• T-cell response against antigens in myelin sheath surrounding CNS neurons causes destruction of myelin

• results in progressive muscle weakness, blindness, paralysis

Type I diabetes

• T-cell response against β cells in the pancreas causes destruction of the cells and insulin deficiency

• results in high blood sugar

Rheumatoid arthritis

• T-cells initiate an immune response against autoantigens in the synovial membrane of joints

• inflammation spreads to bone and cartilage

• results in pain, reduced function and disability

Other genes predispose to autoimmunity

• genes that affect autoantigen availability and clearance

• genes that affect apoptosis

  • deficiencies with apoptosis results in a longer duration immune response

    • excessive tissue damage may mean self-antigens are available for longer

    • inflammation is present for a longer duration

• genes involved in signals that control lymphocyte activation

  • reduced function of negative regulators (that wind-down an immune response) may lead to longer lasting responses (with the same outcome as above)

  • dampened signaling from T-cell/B-cell receptor means fewer cells negatively selected

• genes involved in the development of Tregs

Environmental factors that may contribute to the development of autoimmunity

• the hygiene hypothesis

• vitamin D deficiency

• molecular mimicry in the case of rheumatic fever:antibodies produced against a group A strep infection that goes untreated can cross-react with self-proteins in heart, skin, joints, and brain

The hygiene hypothesis

improvements in hygiene and sanitation practices in developed countries are correlated with an increased incidence of allergies and autoimmune disorders

Development of Cancer

• result from the accumulation of mutations that collectively result in uncontrollable cell division

• as a cell accumulates mutations, it becomes different to a normal cells and such “non-self” cells are detected by the immune system

  • an important job of the immune system is to detect and eliminate early tumor cells

• therefore, cancer-promoting mutations include mutations that enable a cell to evade the immune system

Leukemia

• malignant cells arise in the early blood forming progenitor cells in the bone marrow, which affects circulating blood cells

• cancerous cells accumulate in the bone marrow and crowd out normal cells, resulting in a decreased output of normal blood cells

• cancer can arise in progenitors of myeloid lineage (myeloid/myeloblastic leukemia) or progenitors of lymphoid lineage (lymphoid/lymphoblastic leukemia)

Lymphoma

• malignant cells arise from lymphocytes (B cells or T-cells)

• hodgkin lymphoma or non-hodgkin lymphoma

Tumor antigens

antigens present in tumor cells that stimulate an immune response

Tumor associated antigens

antigens that are also present in normal cells, but at a different concentration

Tumor specific antigens

also called neoantigens, antigens that are not present in normal cells

Cancer/Testes antigens

antigens that are normally only expressed in the testes or during fetal development (i.e., the immune system has not seen the antigens before and will recognize them as foreign to the body)

Monoclonal antibodies

• bind to antigens on tumor cells and can:

  • perform natural functions associated with antibodies, including opsonization and ADCC of tumor cells

  • promote killing of tumor cells by a linked toxin

  • act as checkpoint inhibitors

Adoptive cell transfer (ACT)

a patient’s own T-cells with anti-cancer activity are expanded in the lab and re-infused into the patient

• the T-cells may or may not be genetically modified in the lab

Chimeric Antigen Receptor T-cell (CAR T-cell) therapy

• T-cells are removed from a patient and genetically engineered in the lab to express a chimeric antigen receptor

• antibody binding site is designed to bind to a tumor antigen with high affinity, and it is fused to intracellular sequences that provide signals for T-cell activation and co-stimulation

• genetically modified T-cells are re-infused back into the patient, bind to the timor antigen, and attack the cancer cells

• four CAR T-cell therapies are FDA approved for clinical use, and there are more than 800 ongoing trials

Indicate whether the following statements are true or false

a. secondary immune responses take the same amount of time as primary immune responses to become effective— false

b. on secondary exposure to an infectious agent there is reduced mortality— true

c. only immune responses made in mucosal secondary lymphoid tissues can provide protective immunity—false

d. if an individual acquires a second cold in the same season, it will most likely be caused by a different type of cold virus—true

e. plasma cells generated in a secondary immune response have longer life spans than those made during a primary immune response—false

f. during a primary immune response, only memory B cells are generated—false

Which of the following statements are true regarding immunological memory?

• during a primary immune response, effector B cells outnumber memory cells

• a small population of plasma cells secretes pathogen-specific antibody long after pathogen clearance from the body

• memory T cells and memory B cells originate in secondary lymphoid tissue through clonal expansion

• memory B cells generated in secondary immune responses are more effective than memory B cells made in primary immune responses because of affinity maturation

True statements about FcγRIIB1

• FcγRIIB1 may induce apoptosis in both naïve B cells and plasma cells

• FcγRIIB1 binds to IgG complexed with antigen

• FcγRIIB1 expression limits subsequent immune responses to pathogens, such as influenza, that mutate frequently

All of the following contribute to the establishment and maintenance of long-lived memory B cells

• replenishment of memory population by cell division

• isotype switching

• somatic hypermutation

• interaction with stromal cells in the bone marrow

Memory T cells

• do not require co-stimulation through CD28

• do not undergo somatic hypermutation

• do not undergo isotype switching

Naïve T cell

expresses CD45RA and has a high threshold for activation

Tfh cell

participates in efficient cognate interactions with memory B cells

Central memory T cell (Tcm)

expresses CCR7 and has a low threshold for activation

Resident memory T cell (Trm)

remains in previously infection peripheral tissues and does not recirculate

Effector Memory T-cell (Tem)

lacks L-selectin and CCR7 and recirculates to non-lymphoid tissues

All of the following are descriptive of inactivated virus vaccines

• formalin-treated

• heat-treated

• irradiated

• pathogenic virus required

Smallpox

vaccine is composed of a replicating virus

Hepatitis B virus

recombinant subunit vaccine generated in yeast cells

Rotavirus

fecal-oral route of transmission; contains 11 genomic segments of double stranded RNA

Polioviurs

fecal-oral route of transmission; vaccine is composed of a replicating virus

Influenza virus

rapidly evolving RNA virus requiring new vaccine annually

All of the following statements about polioviruses are correct

• vaccines are produced in both inactivated and live-attenuated forms

• the oral poliovirus vaccine is composed of three live-attenuated viral strains

• if genetic reversion of strain 3 occurs when the virus is replicating the vaccinated people, pathogenesis may occur

• in the US, the recommended vaccine for poliovirus is the inactivated poliovirus vaccine (IPV)