Immune Regulation, transplant immunity, and Hypersensitivity Flashcards
B-1 Cells
Do not interact w/ CD4+ Th cells - do not form germinal centers
Mediate responses to T cell independent Ag (i.e. repeateing subunit, pathogen capsular polsaccharides) - some Ag that can crosslink a large number of BCRs simultaneously
B-1 cells are rare in infants but increase in number until ~5 y/o (infants respond poorly to purified capsular polysaccharide Vax - S. pneumoniae and H. influenzae susceptible)
B-1 cells rapidly secrete IgM after activation
Also do not class switch and do not produce memory B cell
What type of infections are asplenic individuals susceptible to?
Infections with encapsulated bacterial pathogens -
anticapsular IgM is made by splenic B-1 cells - promoting complement-mediated C3b-opsonization of encapsulated microbes
S. pnuemoniae and clinical consequences of B-1 cells and TI Ags
Secondary immune responses and immunologic memory
Ab feedback inhibition
BCR/FcgR
simultaneous
engagement
Inhibits activation of memory B cells
Erythroblastosis fetalis (or hemolytic disease in newborn after birth)
Caused by ABO or Rh incompatability
Hb recycling
Fas/FasL
Fas = death receptor
T/B cells become more sensitive to Fas-mediated killing if they remain activated for a long period of time (AICD = activation-induced cell death)
FasL - main mech for removal of unwanted lymphocytes during development
Autoimmune lymphoproliferative syndrome (ALPS)
Defects in Fas or FasL
Chronic, non-malignant lymphoproliferative disease
ALPS results from failure to kill activated and self-reactive T/B cells
Pt’s present w/ enlarged lymph nodes, spleen and/or increased incidence of autoimmune
Rogam
IgG to Rh factor - preventing maternal Abs from binding to fetal RBCs - by activating Ab feedback
Turns off naive B cells - would turn on membory T cells
How do APCs turn old effector T cells off?
Old T cells will express CTLA-4 or PD-1 on their surfaces - engaged by APC B7 or PD-1L
What drives development of CD4+ Th0 to Treg cells?
Exposure of a CD4+ Th0 cell to TGF-beta during activation promotes production of the FoxP3 transcription factor - drives development
Immune dysregulation polyendocrinopathy enteropathy (IPEX)
Genetic defects in the FoxP3 gene - primary immunodeficiency
Fatal autoimmune disorder directed against variety of tissues
Autoimmune polyendocrinopathy (early-onset insulin-dependent diabetes mellitus, autoimmune thyroiditis, and/or autoimmune hemolytic anemia/thrombocytopenia
Typical IPEX Pt is a young male presenting w/ enlargement of the secondary lymphoid organs, insulin dependent diabetes, nail dystrophy, and autoimmune dermatitis
Illustrates importance of Treg in maintaining tolerance and protecting against autoimmune
What cytokines do Tregs produce that suppress activity of other effector CD4+ T cells?
IL-10 and TGF-beta
Tregs in the gut mucosa
Th2 dominant environment
Mucosal DC in MALT promote Th0 to Th2 differentiation
Mucosal macrophage have reduced signaling activity between PRR and NF-kappabeta - results in less inflammatory cytokine production in response to PAMPs
IL-10 dampens Th1 responses - limits immune responses to food and normal microbial flora
GM-CSF and IL-3
Stimulate growth and differentiation of bone marrow stem cells
IL-5
Increases eosinophil production from the bone marrow
Neuro-endocrine regulation of innate and adaptive immune responses
TNF-alpha, IL-1beta, and IL-6 cross BBB and stimulate hypothalamus to release CRH
Increases cortisol release which acts on macrophages glucocorticoid receptors to reduce inflammatory cytokine gene transcription
T-cell negative selection
T cell clonal anergy and failure of clonal ignorance at an immune privileged anatomical site
Type I hypersensitivity reaction
Starts immediate - peaks 30 minutes
Ag-specific IgE binds to Fcepsilon receptor-I (FceRI) on surface of mast cells, activated eosinophils, and basophils
- MOST Importantly – most hypersensitivity reactions require sensitization – pre-exposure to the antigen eliciting the response.
Type II hypersentivity reaction
Ag-specific IgG (and/or IgM) = starts 1-2 hrs, peaks at 4-6 hrs.
Binds to ECM or host cell surface-associated allergen
ECM or cell surface-bound allergen-Ig complexes activate complement, release anaphylatoxins, and inflammation, which mediate the reaction
- MOST Importantly – most hypersensitivity reactions require sensitization – pre-exposure to the antigen eliciting the response.
Type III hypersensitivity reaction
Ag specific IgG (and IgM) = 1-2 hours, peaks 4-6 hrs
Binds to soluble allergen in blood or tissue spaces
Immune complexes precipitate on vessel walls - particularly in the skin, renal glomeruli, and joins, which activates complement
- MOST Importantly – most hypersensitivity reactions require sensitization – pre-exposure to the antigen eliciting the response.
Type IV hypersensitivty reactions
Delayed type hyersensitivity = starts 24-hrs and peaks 48-72 hrs
Ag specific effector T-cells (usually Th1, Th17 and/or CD8+ CTL) react against either soluble or cell-associated allergens, which induces inflammation and mediates the hypersensitivty reacdtion
- MOST Importantly – most hypersensitivity reactions require sensitization – pre-exposure to the antigen eliciting the response.
Examples of IgE-mediated allergic rx’ns
Sensitization immediate response
Sensitization late response
Asthmatic response to inhaled allergen
Clinical presentation and location of allergen exposure
Type II Penicillin hypersensitivty
Type IV reactions and tuberculin rx’n
What receptors are upregulated as CD4+ in “old” T cells
CTLA-4 and PD-1
Factors that allow Treg cells to inactivate self-reactive effector CD4+ T cells
FasL, FoxP3, TGF-beta receptor
AIRE transcription
Autoimmune regulator - expression of tissue specific Ag presented by interdigitating DCs or epithelial cells ectopically expressing antigens specific to other tissues
Where does class switching occur?
The germinal center of secondary lymhpoid tissue
Why B-1 cells do not class switch, undergo affinity maturation
A. Eosinophils
IL-5 is involved in making eosinophils and activating them
B. Recurrent infections
Blocking B7 = APCs expressing B7 co-stimulatory factor is needed to activate T cells (binds to CD28 on Tcell to activate it)
Also binds CTLA-4 (expressed by aging T cells) - to undergo apoptosis
An immunological hypersensitivity reaction that occurs within 30 minutes of antigen exposure is classified as which type of hypersensitivity?
Type I
Type IV hypersensitivity
In Type I hypersensitivity, the cytokine IL-4 is directly involved in?
Ab class switching in activated B cells
Also drive T cells to Th2 cell differentiation
In type II - IL-4 is involved in complement activation following allergen engagement
Complement C3b
IgG formed after initial response = hemolytic anemia/thrombocytopenia
An outdoorsman has been bitten by a rare, but very venomous snake. The only therapeutic option is to administer antivenin generated in horses. About 5-days after the injection, the patient begins to experience fever, vasculitis, arthritis, and nephritis. This immunological reaction is best described as?
Type III hypersensitivity reaction
(deposition of immune complexes - soluble Ag)
MHC Class II
A healthy person with a newly diagnosed allergy to cat dander visits a home with many cats. Thirty minutes after arrival, the person is having difficulty breathing because of airway constriction. The person leaves the home and symptoms improve; however, 8-hours later the symptoms return and stay about 4-5 hours. This type of immunological reaction at the 8-hour stage is best described as:
A. Reaction primarily caused by histamine release
B. Reaction caused by the production and release of leukotrienes
C. Reaction involving pre-formed memory Th1 cells
D. Reaction involving pre-formed IgG Abs specific to Ag
B. Reaction caused by the production and release of leukotrienes
Which granulocyte involved in hypersensitivity reactions does not constituively express the IgE receptor?
Eosinophils
Produce major basic protein - toxic to multicellular parasites and host cells
Study
Study
C. Mast cells
E. Histamine
Late phase mast cell response
B and D - Basophils and Mast cells
Eosinophils
Control of Eosinophil response
B. IL-4
Allergen desensitization
IgG4 is involved in a down regulation of the inflammatory response
C. IgG
Same as Type III
IgE in type I
Memory T cells in Type IV
D. Hapten
C. IgG
What favors the formation of small immune complexes?
When Ag conc.»_space;> Ab con.
Pathology of Type III hypersensitivty reactions
Arthus reaction
Type IV hypersensitivity
I.e. poison ivy, toxic metal contact dermatitis, and tuberculin rx’n
Tuberculin reaction
Type IV hypersensitivity to metals
Transplantation antigens
HLA class I and II; MHC
Alloantigens
Antigens that vary between members of same species
Alloreactions
Immune response provoked by alloantigens
Graft-vs-host-disease (GVHD)
Alloreaction that arises from mature T cells in the grafted bone marrow (or rarely in solid organs) that attack and reject the recipients health tissue
Types of transplants
Autologous
Syngeneic (transplant between identical twins; inbred animals)
Allogeneic (human to human; not identical twins)
Xenogeneic (pigs most suitable)
Ags responsible for transplant rejection
ABO and Rh D
HLA-human leukocyte Ag (MHC I/II)
Minor histocompatibility Ags: Non-MHC, normal cellular proteins - rx’n not as severe as allo-MHC mediated rejections
RBCs do not have HLA Ag’s
Direct Coomb’s test
Detects in vivo Ab/RBC Ag rx’ns
Mixed lymphocyte Rx’n test for potential transplant rejection
Hyperacute transplant rejection
-Caused by pre-existing Abs
-Occurs within hours
-No reliable way of reversing
Abs to ABO or MHC allo-Ags (type II hypersensitivity rx’n) bind to graft vasculature eliciting complement activation
Can be prevented by the “cross-match-assay” to discover allo-reactive Ab
Becuase of typing - does not happen anymore in clinic
Acute transplant rejection
-Can be cell mediated and/or alloAb mediated
-Caused by recipient allo-reactive CD8 and CD4 T cells specific for inconsistencies in donor MHC from donor DCs
-Takes days to develop
-Can be reduced/prevented w/ immune suppression
-Type-IV hypersensitivity rx’n
Chronic transplant rejection
-activation of alloreactive Abs and T-cells
-Ultimately results in vascular occlusion and interstitial fibrosis
-Occurs months/years after transplant
Mechanisms of Graft Rejection
Direct allorecognition/rejection:
DCs of an inflamed transplant undergoing rejection are activated - migrate to lymph where they settle into T-cell zone and present Ag (common in acute rejection)
Indirect:
Some donor-derived DCs that migrate to draining lymphoid tissue die there by apoptosis - membrane frags containing HLA are taken up by recipient DCs
Bone marrow transplant
Myeloablative therapy - cytotoxic drugs and irradiation to prevent rejection by recipient T cells and kill all hematopoietic cells w/i recipients bone marrow
A critical feature of the T-cells of the patient’s new immune system is their positive selection by thymic epithelial cells expressing
Graft-versus host disease in bone marrow transplants
Because the number of mature T-cells in the transplant is limited, the duration is usually restricted to the first few months after transplant
Can be easily demonstrated experimentally by the mixed lymphocyte reactionS
GVHD tissue reactions and grading and diagnostic sxs
Autologous bone marrow transplant
Commonly used Tx option for lymphomas - unless spread to marrow
CD34-expressing stem cells are separated by leukophoresis after stimulation w/ granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)
ABO Ags
Glycoacetyl transferase adds terminal AA
ABO Ags and Abs
Chart
Effect of HLA Matching on Kidney Graft Sruvival
Cross-matching test
Recipient serum and donor RBCs
Positive agglutination shown
Indirect Coomb’s test
Detects in vitro Ab/RBC Ag reactions (i.e. blood transfusion, antenatal Ab screening)
Mixed lymphocyte Rx’n
Increased radioactivity = increased proliferation of recipient cells = MHC mismatch
Thrombosed artery secondary to humoral chronic rejection of kidney
Direct pathway of allorecognition
The type of transplant rejection where pre-existing IgG antibodies in the recipient’s serum reacting to a donor’s solid organ transplant is closest to which type of Hypersensitivity reaction?
Type II hypersensitivity reactions
A patient has received an allogenic hematopoietic stem cell transplant and is now experiencing a significant rash, increased bilirubin, and diarrhea. Which immune component type is most responsible for this reaction?
D) Donor’s T-cells
A key event specific to chronic rejection in solid organ transplantation is?
E) Interstitial fibrosis
A skin graft is performed between two mice with the same genetic background. This type of transplant is called?
Syngeneic
C. RBC autoimmunity
Direct tests for autoimmunity or drug-induced immune-mediated penicillin rx’n
Acute rejection of heart
A. Hyperacute
Type II - IgG mediated hypersensitivty - primary cause of hyperacute rejection
Difference in direct vs. indirect allo-recognition of HLA
Sxs of graft-vs-host disease
Maculopapular rash to generalized erythema w/ blistering and desquamation (depending on severity)
Elevated serum bilirubin
Diarrhea (w/ or w/o obstruction in severe cases)
CTLA-4
Used by APCs
