Immuno Lec 9 - Immunoregulation

Question 1

the importance of regulating the immune system

Answer 1

-excessive response= allergies, autoimmunity, and lymphoid tumors can occur

-defective response = increased infections (bc not responding against robust pathogen), increased cancers (as you age the immune system decreases, which is why most cancer is diagnose in the older population

Question 2

evidence of immunological tolerance

Answer 2

• Fusion of the placentas of
  dizygotic twin calves results in
  the development of calf chimeras
• Hematopoietic stem cells from
  each animal colonize the bone
  marrow of the other
• Each chimera is tolerant to its
  twin’s cells and will accept a skin
  graft from its twin despite the
  genetic differences

Question 3

T cells are rendered tolerant of self antigens

Answer 3

-Failure to do so risks autoimmune disease

There are two mechanisms to induce T cell tolerance:
* Central tolerance

• Strongly self‐reactive T cells (TCRs that bind self‐derived peptides with high affinity) are killed during thymic
  development
• Peripheral tolerance
• Weakly self‐reactive T cells (TCRs that bind self‐derived peptides with low affinity) are “turned off”
• These can be activated to kill cancerous/dangerous self
• Note: this means that a natural T cell response against cancerous cells is relatively weak

Question 4

central T cell tolerance

Answer 4

• How the thymus induces central T cell tolerance by negative selection
• Most surviving T cells are unreactive to autoantigens but can respond to foreign antigenic peptides in association with MHC molecules because of positive selection

Question 5

peripheral T cell tolerance

Answer 5

Peripheral tolerance through clonal anergy will develop if a TCR is stimulated by an epitope in the absence of simultaneous co‐ stimulation through the CD28/CD80 or CD28/CD86 pathway.

Question 6

regulating T cells at the immunological synapse

Answer 6

-The major “accessory” molecules of T cells, so called because they participate in responses to antigens but are not the receptors for antigen. Cytotoxic T Lymphocyte Antigen‐4 (CTLA‐4; aka CD152) is a receptor for B7 molecules that delivers inhibitory signals and has a role in shutting off T cell responses. VLA molecules are integrins involved in leukocyte binding to endothelium. APC, antigen‐presenting cell; ICAM‐1, intercellular adhesion molecule‐1; LFA‐1, leukocyte function– associated antigen‐1; MHC, major histocompatibility complex; TCR, T cell receptor; VLA, very late antigen

Question 7

regulating T cells at the immunological synapse; practical application

Answer 7

• To treat cancers
• Tumour‐infiltrating T cells become highly activated due to the presence of excessive target antigens so they up‐regulate CTLA‐4, which causes them to get shut down prematurely
• An antibody to block signaling through CTLA‐4 can prevent this
• Such an antibody is called an “immunological checkpoint inhibitor”
• This prolongs T cell activation and, therefore, killing of cancer cells

Question 8

regulatory T cells (Tregs, CD4+CD25Foxp3+)

Answer 8

• The production and functions of regulatory T cells
• They are generated by the combined actions of IL‐2 and TGF‐β as well as the presence of retinoic acid
• They characteristically produce the suppressive cytokines TGF‐β, IL‐10, and IL‐35

Question 9

T helper-17 (Th17) cells

Answer 9

-The generation of Th1 and Th17 cells depends upon the production of IL‐12 or IL‐23 by antigen‐presenting cells. Th1 cells promote cell‐mediated responses, Th17 cells promote innate responses via secretion of interleukin‐17 (IL‐17)

Question 10

B cell tolerance

Answer 10

• B cells are harder to tolerize than T cells (this is why most autoimmune diseases are primarily antibody‐mediated)
• Tolerization of CD4 + helper T cells = tolerization of helper‐dependent B cell responses (i.e., against protein‐derived antigens)

-Note: a BCR must be expressed for a
B cell to be positively selected (‘tonic’ [baseline] signaling is required from the presence of BCRs)

-low dose antigens (These are usually self antigens (self‐recognition = negative selection))

Question 11

very low/high doses of antigen may cause tolerance

Answer 11

-The ability of different doses of antigen to induce peripheral tolerance. Both very low and very high doses can induce tolerance.
Moderate doses, in contrast, usually induce an immune response

Question 12

negative feedback regulation of antibody responses

Answer 12

• The presence of high concentrations of antibodies/immunoglobulins generally suppresses new B cell responses
• IgG antibodies tend to suppress the production of both IgM and IgG
• IgM antibodies tend to suppress only the synthesis of IgM
• Specific antibodies tend to suppress a specific immune response better than nonspecific immunoglobulins
• Suppression is the result of antibodies binding to an inhibitory B cell receptor (i.e., CD32b; aka FcγRIIb)

-Cross‐linkage between a BCR and CD32, an Fc receptor, by antibody and antigen can turn off a B cell by activating a phosphatase that in turn blocks signaling by tyrosine kinase

• The presence of high concentrations of antibodies/immunoglobulins generally suppresses new B cell responses

Question 13

negative implication of antibody mediated regulation of B cell responses; maternal antibodies

Answer 13

-The presence of maternal antibodies/immunoglobulins in a newborn animal effectively delays the onset of synthesis of new immunoglobulins/antibodies through a negative feedback process. This reduces the efficacy of vaccines in neonates; thus, the rationale for delaying vaccination

Question 14

negative implication of antibody mediated regulation of B cell responses; myelomas

Answer 14

• Myelomas = cancerous plasma cells
  (Greek myelo‐ ‘marrow’ and ‐oma ‘tumor’)
• They produce very large quantities of immunoglobulins
• This causes negative feedback inhibition of B cell responses
• Patients become susceptible to infections due to weak
  antibody responses

Question 15

positive implication of antibody mediated regulation of B cell responses; hemolytic disease

Answer 15

• Hemolytic disease in human newborns
• Caused when a mother who lacks the Rhesus (Rh) blood group antigen gives birth to a child that is Rh +
• If nothing is done, at the time of birth there is mixing of blood and
  the mother develops Rh‐specific antibodies
• If a subsequent child is Rh +, these antibodies will cross the placenta and lyse red blood cells, causing anemia
  (sometimes leading to death)
• If a mother receives antibodies against Rh just before initial exposure
  to Rh + fetal red blood cells at birth, she will be completely prevented
  from making Rh‐specific antibodies of her own (and subsequent babies won’t be at risk of developing hemolytic anemia)
• Anti‐Rh destroys fetal RBCs before the mother responds, plus, there is negative feedback inhibition of B cell responses

Question 16

tolerogenic macrophages

Answer 16

• Activation of macrophages in the presence of IFN‐γ leads to the development of pro‐inflammatory, classically activated M1 cells
• Activation of macrophages in the presence of IL‐4 or IL‐13, leads to the development of M2 cells
• M2 cells participate in tolerance induction, suppress inflammation, and participate in tissue repair
• M2 cells are the predominant macrophage population in the lungs to prevent chronic inflammation in response to constant exposure to inhaled environmental antigens

Question 17

tolerogenic dendritic cells

Answer 17

• Immature dendritic cells (DCs) that have not been exposed to inflammatory stimuli express low levels of co‐stimulatory molecules
• If they present antigens to T cells, they either induce anergy or cause them to become Tregs
• This is a mechanism to promote self‐tolerance
• Apoptotic cell death is non‐inflammatory and a normal physiological function
• Local immature DCs will phagocytose and present antigens from these cells and induce tolerance
• Tolerogenic dendritic cells in the liver are responsible for the phenomenon of oral tolerance (i.e., preventing immune responses against food antigens and normal microflora)
• Antigens that enter the circulation from the gut first pass through the liver via the portal vein
• The liver has high numbers of tolerogenic DCs that intercept and present these antigens

Question 18

indoleamine 2,3-dioxygenase (IDO) and tolerance

Answer 18

• One mechanism used by tolerogenic cells is the production of IDO
• IDO promotes degradation of the amino acid tryptophan, causing local depletion
• Tryptophan is an essential amino acid that is needed in large quantities by T cells
• T cells deprived of tryptophan undergo apoptosis

Question 19

the neuroendocrine-immune axis

Answer 19

• Helps explain how stress can impact immunity
• Reasonable stress of short duration (e.g., exercise) may enhance immune responses
• Prolonged/excessive stress =
  immunosuppression (e.g., contributing factor for shipping fever in cattle; pneumonia caused by
  multiple pathogens following prolonged transport)

Question 20

immunoprivileged sites

Answer 20

• Anatomical locations where immune responses are restricted and/or tightly regulated
• Originally identified as sites where transplanted foreign tissues could survive for prolonged periods
• Critical tissues that could be damaged by excessive inflammation

-examples= brain (BBB), eyes, testicles and ovaries, placenta and fetus

• A medical procedure that takes advantage of this is cornea transplants

Question 21

the hygiene hypothesis

Answer 21

-A theory to explain the increased incidence of allergic diseases in highly developed countries like Canada. The basic concept is that our lifestyles are now too “clean”. Exposure to some infections may promote the development of immunological tolerance. A significant reduction in the rate of infections among children is thought to result in less immunological tolerance, which promotes hypersensitivities like allergies and asthma, and autoimmune diseases.

• Now better known as ‘Targeted Hygiene’