Download Immuno Outline Test #3 Lectures 19/20: Mechanisms of Tolerance and

Immuno Outline Test #3
Lectures 19/20: Mechanisms of Tolerance and
Autoimmune Disease
B cell Central Tolerance
 Negative Selection
o BM stromal cells express self-Ag on surface
o If strong binding to the multi-valent self-Ags as BCR’s crosslink
apoptosis
o If strong linking to soluble self-Ags w/o crosslinking of BCR anergy
o Strong binding maintains activation of RAG 1/ 2  rearranges L chain
(receptor editing)
o No recognition of self-Ags survival (cells enter periphery as
IgM+IgD+ *different than T cells
o Surviving B cells go to follicles, anergic B cells do NOT go to follicle
*diff than T cells
 Positive Selection
B cell Peripheral Tolerance
 4 Mechanisms to prevent against auto-immunity:
o Signal 1  anergy
o CTLA-4 anergy
o Fas/FasL pathway apoptosis
o Tregs reside in lymph, infected site
 Follicular Exclusion: CXCR5- anergic B cells encounter self-Ag in T cell zone
 If B cells react to self-reactive Ag aptoptosis (Fas expression)
 Apoptosis of Anergic Self-Reactive B cells (especially in Germinal Center) 
will die!! *not a method of autoimmunity
T cells Central Tolerance
 Thymus- eliminates self-reactive T cells
o Positive Selection: cortex
 Positive selection for T cell who’s TCR binds MHC on thympic
epithelial cell  survives, becomes single-positive, upregulates
CD3
 If no MHC interaction (defect) apoptosis
o Negative Selection
 Test TCR for self-reactivity
 Surviving SP T cell interacts with Medullary Thympic Epethial
cells (MTEC) produce AIRE (self-Ags)
 can also interact w/ DCS and Macs
 If strong MHC binding to self-Ag apoptosis
 If weak MHC binding to self-Ag  survival (only 10%)
 Surviving T cells (Naïve Mature) reside in T cell zone
T cell Peripheral Tolerance
 The surviving T cells (Naïve Mature) need 3 signals from mature DC* critical
to immune response
o Signal 1: microbe  peptide
o Signal 2: PRR (innate receptor) and cytokine receptor expresses B7
on APC
o Signal 3: cytokines
o T cell receives 3 signals Activated (effector Tcell)  TCL or Th1
o If only get signal 1 T cell anergy
o T cells can differentiate into CD4 cells and CD8 cells (based on
cytokine secretion)
 IL-12 TH1, secretes IFN-gamma Tc1
 IL-4 Th2, secretes IL-4, IL-13
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If Self-Ag is presented on mature MHC
o T cell gets activated, must be inhibted by CTLA-4, Fas/FasL(tissues)
o CTLA-4 gets expressed on self-reactive T cell, binds B7 (instead of
CD28) blocks TCR or cytokine signals apoptosis
o Fas/FasL gets expressed on self-reactive T cells kill each other
o * potential for autoimmunity= breakdown of CTLA-4 or Fas/FasL
o Immunosuppression
 Natural T regs (Lymphoid): express CD25 early and FOXP3+
 Use NFkB, and IL-2 for Treg developement FOXP3
expression
 Contact dependent, supressors
 Induced T regs (Tissues)
 Secrete TGFbeta, upregulates Fox3P suppressor cell
 Secrete IL-10 no Fox3P expression, secretes IL-10
Treg 1 (Tr1)
 Secrete mucosal Ag or immature DC and low dose Ag
Th3, secretes IL-10 and TGF beta.
 Cytokine dependent suppressors, secrete cytokies
Diabetes
 T cells destroy beta cells
 B cells produce autoantibodies (diagnostic marker for high risk diabetes85% predictor, can intervene with drug
 Population of beta cells decreases, at 10% left, plasma glucose increases and
beta cells enter “honeymoon” phase and proliferate/grow
 If not given insulin, beta cells population will then continue to decrease
 Fas/FasL, MHC, perforin/granzyme, TNF-alpha and TNF receptor all involved
in beta destruction
 Self reactive T cells in the pancreas lymph nodes
 MHC connection (IDDM1- insulin dependent diabetes mellitus
o If strong interactions between HLA, Ag, and TCR, then self-reactive T
cell eliminated
o If floppy binding, weak TCR signal, reactive T cell survives and
escapes central tolerance
 Activation of self-reactive T cells
o “molecular mimicry”- microbes can elicit signals 2 &3 (B7, innate
receptor, cytokines)
o Other sources: Ag source: Wheat (gluten), cow’s milk (insulin)
o Ag and TNF source: viral components, wheat (gluten)
 Self Reactive T cell escapes methods of tolerance by:
o 1- have mature APC (already have signal 1), don’t see anergy
o 2- susceptibility of allele (IDDM!2), CTLA 4 is diminished/defective
o 3- deficiency in Tregs (IDDM10)
 IL-10 levels, not enough IL-10 for suppression, provokes
immune response
 CD80/CD86
Other Auto-immune Diseases
 Autoantibodies mediate disease by recognizing self-Ag, forming immune
complex, complexes build up compliment (vasculitits, nephrititis)
 Activation of Self-Reactive B cells
o Reside in T cell zone, encounter self-Ag (nothing to rescue cell)
apoptosis
o Activated Self-reactive CD4+ T cells rescue self-reactive anergic B cells
(CD40 Ligand signaling)
o **No method of rescuing T cells**
o Rescued Self-Reactive B cell expresses CXCR5, enters follicle
Immunotherapy for Autoimmunity
 HLA-DQ/DR: Class II MHC
 Vitamin D sways response from inflammatory (Th1, Th17, beta cell
destruction) to Th2 anti-inflammatory response (Tregs, IL-10) suppress
disease onset
 Oral Tolerance in mucosa- dose dependent
o High Dose Tolerance: Several peptides expressed on APC, bind TCR
(w/o costimulation) anergy
o Low Dose Tolerance: TGF beta stimulates DC’s to activate Tregs (Ag
w/o co-stimulation), suppression of T cell
 Potential for systemic tolerance
o So in the oral tolerance, it’s always w/o co-stimulation?
 Gluten Tolerance
o If gluten is improperly digested to gliaden peptides, they become
negative charged and bind strongly to MHC (HLA DQ w/ Celiac
Disease) generates inflammatory response
o IEL’s also secrete cytokines (IFNgamma)  Th1 (inflammation)
 Ag-Coupled Cell-Induced Tolerance
o Crosslink chemicals w/ peptides on splenocytes direct tolerance
anergy
o MBP peptides + ECDI-fixed PBL prevents onset of EAE
o If Ag coupled cell undergoes apoptosis indirect tolerance peptide
on apoptotic bodies induced anergy (Prevents epitope spreading?)
o EAE , autoreactive CD4+ T cell enters tissue, releases cytokines
destroys myelin produce more Ag leaky BBB activate other
peptide, activates more T cells (reason for relapsing, remitting) in MS
 Anti-CD20 Antibody
o Rituximab: inhibits B cell function (reduces amount of auto antibody)
 Antigen-Specific Immunotherapy
o Main goal: attack certain group of targeted cells cell death/anergy
o Problem: allergies against soluble peptide
o High doses of soluble peptides anergy
o T cell-reactivation w/ peptide activation induced cell death
Hypersensitivities
Type I
 “immediate hypersensitivity”
 rapid degranulation of mast cells
 wheal and flare- blotches of raised lesions
 effects skin, respiratory, GI, systemic
 allergen exposure induces Th2 (instead of Th1) response isotype switching
(IgE) instead of IgG
 Aptopic (predisposition for allergic response) increased affinity of mast
cell FceR, higher affinity for IgE, and remains on surface longer
 Allergen binds B cell activates Th2 cell produces IgE IgE binds FceR on
Mast cell
 Second exposure to Allergen allergen binds IgE on mast cell allergen
cross-linkage of IgE activates mast cell degranulation
 Immediate response: premade granules
 Late phase response: cytokines
 Epinephrine: primary treatment for anaphylaxis cAMP, PKA, in mast
cells (prevents mast cell degranulation)
Type II
 Antibody-mediated hypersensitivity
 Against Cell surface Ags
 Complement – classical pathway, “frustrated phagocytosis”, release digestive
enymes and ROS onto tissue
 Fc receptor mediated recruitment and activation of inflammatory cells
 Opsonization & phagocytosis: circulating cells coated with Abs against cell
surface Ags neutrophils, macs capture coated cells (phagocytosis) – NO
frustrated phagocyosis
o Ex: ABO group, Rh factor
 Ab-mediated cell dysfunction
o Binding of Ab to cell surface Ags impair normal function (no
inflammation) ex: hyperthyroidism, Myasthenia gravis
Type III
 Immune Complex Mediated Hypersensitivity
 Abs against soluble Ags
 ICs deposit in kidney, blood vessels, Joints
 Compliment activation activates Neutrophils, bind to Fc frustrated
phagocytosis
 Normal IC clearance: C1q binds to ICC3b binds to Agbound C3b binds to
receptor CR1 on RBC RBC goes to liver, spleen, Factor I loosens IC from
RBC gets phagocytosed
 Persistant Ags (infection, autoimmunity, inhaled Ag-mold) persistant IC
complexes
 SLE (Systemic Lupus Erythematosus)
 Normal Clearance of Apoptotic cells
o Opsonized by Macrophages, non-inflammatory, tolerance
 Impaired Clearance of Apoptosis
o Deficiency in (or AutoAb against) one of opsonization factors
apoptotic body not clearned undergoes necrosis stimulates
inflammation
Type IV
 T cell Mediated Hypersensitivity
 Abnormal T cell responses to Ags
 Autoimmune disease (Lupus)
 Delayed Type Hypersensitivity (CD4+ Tcells)
o Granulomatous Hypersensitivity
 Chronic T cell response to chronic Ag, IFN gamma activates
macs to create granulomas
 TNFalpha: recruitment of macs to granuloma (maintain)
 Sensitization step: CD4 T cell memory
o Contact Dermatitis (T cell mediated allergic response)
 Poison Oak, small Ags, conjugate w/ self protein
 1. Sensitization Step: initial contact w/ Ag (skin allergens),
small amount contact Ag T cell memory (2 weeks)
 first encounter: no reaction w/in 2 weeks
 2. Elicitation Step
 Re-exposure to contact Ag
 Memory response, macrophage inflammatory cytokines
clinical symptoms (localized inflammation)
 T cell Mediated cytolysis (CD8+ T cells)
o FasL-Fas Pathway apoptosis
 Target cells= Fas + (fas on stressed cell)
 Effector= FasLigand
o Peforin/Granzyme

Activate caspase pathwayapoptosis
Blood Group Ags and Transfusions
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Blood Transfusions
o Used to treat hemorrhage, RBC destruction (hemolytic anemia),
inadequate blood cell production in bone marrow
o Requires cross-matching
 Red cells: ABO group, Rh factor, Minor red cell Ags
 White cells: MHC matching
Blood Types
o Inherited antigenic proteins, carbs, glycoproteins on RBC surface
o AA or AO: A antigens on RBCs, anti-B antibodies, receive B or O blood
o BB or BO: B antigen on RBC’s; anti-A antibodies, receive A or O blood
o AB: A and B antigens on RBCS; neither anti-A nor anti-B Ab, receive A,
B, AB, O blood (universal recipient)
o O: neither A nor B Ag on RBC; anti-B and Anti-A Abs; receive O blood
(universal donor)
o True recpient: AB+
o True Donor: ORh Factor
o Hemolytic Disease of the Newborn:
o Problem when mom is Rh-,
o During delivery of Rh+ baby, blood is transferred, and Mom makes
Abs against Rh+ (first baby okay)
o If second baby is Rh+, Mom will attack baby with her Ab(IgG) against
Rh+
o Treatment: Rhogam: doesn’t allow mom to make Ab against Rh+
(immunosuppressor)
Transfusion
o Needed when Hb(hemoglobin) <8 g/dL
o Cross Matching
 Major cross match: tests patients serum for Ab directed against
RBC to be transfused
 Minor Cross match: test donors serum for Ab directed against
recipient’s RBC
 Drop of donor RBC mixed w/ patient plasma
 If patient has Ab against donor red cells, agglutination
 Acetominophen and benedryl given prior to transusion
(reduces minor transfusion reactions)
 Coomb’s Test
 Direct:: used for anemias (looking for Abs bound to
RBC’s), can be caused by certain meds
 Indirect: used for testing reaction for blood transfusion
o Add Ab’s from patients sample to donors RBC’s=
Ab’s bind to RBC
o Add anti-Human IgG binds to Ab’s bound to
RBC agglutination = not compatable
o Transfusion Reactions
 Clinical Symptoms: fever, chills, dark urine, chest pains,
dyspnea, shock, flank pain, oliguria, anuria,
blooding/hypotension during surgery
 Non-immune reactions: contaminated blood, causes immune
response
 Immune reactions: RBC incompatability, Platelet/Leukocyte
incompatability, anti-allotypic Abs
 Acute Hemolytic Reaction
 Most frequent case of transfusion reaction due to ABO
incompatability- Clerical Error!!
 Fever, chills, flushing, hypotension/hypertension,
tachycardia, nausea, burning, bleeding at IV site
 Recipient IgM against donor A/B antigens hemolysis
of donor RBC’s, compliment, form clots, anaphylaxis,
shock, death
 Diagnosis:
o serum of patient appears pink (hemoglobinemia)
o serum biliruben elevated
o dark patient urine (hemoglobinuria)
 Transfusion-Related Acute Lung Injury
 Occurs w/in 6 hours
 Symptoms resemble respiratory distress syndrome
 Nonproductive cough, dyspnea, tachypnea,
hypotension, tachycardia, fever, chills, bilateral nodular
infiltrates on CXR, pulmonary edema
 Immune complexes enter pulmonary vascular bed
vasodilation pulmonary edema
 Allergic Reactions/Anaphylaxis
 Occurs when a person has been pre-sensitized to
allergen, and receives same allergen in transfusion
Transplantation Immunology
 Autologous graft- self graft
 Synthetic graft- graft into different member of same strain
 Xenographic graft- graft into different species
 Allographic graft- different member of same species (different strain)
o Alloantigens- molecules on allograft seen as foreign
alloreactive immune response
o Direct recognition of Alloantigens
 TCR can see allogenic MHC as self, recognizes foreign
peptide
 Or TCR can view allogenic MHC and foreign peptide
 Because all cells have MHC IUsually occurs in CD8+
cells direct lysis
 Strong rejection because of numerous MHC’s on graft,
greater opportunity for APC binding readily activate T
cells
o Indirect recognition of Alloantigens
 APC of recipient (DCs) take up allogenic tissue cell
processes peptide presents to alloreactive T cells by APC
 CD4+ more common, also CD8+ (cross-presentation)
o Graft vs Host Disease (GVHD): donor tissue that has T cells in
itrecognizes recipient molecules as foreign graft attacks
tissues of host
o Non-MHC Alloantigens
 Minor histocompatability antigens (mHA)
 Allograft Rejection
o Hyperacute rejection:
 Occurs w/in minutes to hours after transplantion
 Pre-existing antibodies bind to graft endothelial cell Ags (sell
surface) – same as Type II hypersensivity
 Complement activated, recruits neutrophils, macs
o Chronic Rejection
 T cells Chronic IFNgamma smooth muscle proliferation
(hyperplasia) vessel occlusion (causes damage)
o Acute Rejection
 Involves CD4+, CD8+, and B cells
 Activates complement same response
Immunosuppression and Rejection
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Cyclosporine: inhibits activation of NFAT transcription factor blocks
T cell cytokine production
Rapamycin: inhibits IL-2 signaling blocks lymphocyte proliferation
(no clonal expansion)
Immunodeficiency
 Primary Immunodeficiency Diseases
o Humoral Immunodeficiencies
 Infantile hypogammaglobulinemia (Bruton-Janeway
syndrome)
 lack of Bcell tyrosine kinase gene,
 lack of follicles, lack of B cells,
 few circulating Igs,
 bacterial infections
 Common Variable Immunodeficiency (CVID)
 Normal B cell numbers, defective
differentiation/maturation (Heavy chain gene deletion)
 Abnormal function of T cells (inadequate T cell help)
 Excessive Treg activity
 Low Igs
 Bacterial, fungal, parasitic infections
 Adult onset agammaglobulinemia
o High prevalence of autoimmune disease
o Neoplasmic conditions, GI lymphomas
 Hyper IgM Syndrome
 Lack of CD40L on T cells (no isotype switching)
 IgG, IgA, high IgM
 bacterial infections
 IgA deficiency
 Anti-IgA antibodies, antibodies to milk, other food
antigens
 Bacterial, parasitic (Giardia)
o Cellular (T cell) immunodeficiencies
 Thympic Aplasia (DiGeorge’s Syndrome)
 Depletion of T cell areas
 T cells
 Normal B cell #’s, deficient function
 Igs (IgG)
 viral, bacterial
 Neonatal tetany (hypocalcemia from
hypoparathyroidism)
 Abnormalities of heart, vessels
 Facial dysmorphism, mental subnormality
o Combined Immunodeficiencies
 Severe Combined Immunodeficiencies (SCID)
 “bubble boy”
 thympic apasia, atrophy of lymphoid organs
 T cells,
 variable B cells
 IgG
 all types of infection, chronic/persistant
 Therapies: Bone marrow transplantation, gene thearpy
 MHC deficiencies
 Lack of expression of MHC class I or class II
 Normal/low T cells
 B cell # normal, deficient function
 IgG
 all types of infections
 Ataxia-Telangiesctasia
 rare
 Deficiency of DNA repair enzymes
 Capillary abnormalities (visible in superficial areas)
 Cerebellar ataxia, telangeictasia of skin, conjunctiva
 Thymic hypoplasia, T cell deficiency, Ig’s (IgA)
 Wiskott-Aldrich Syndrome
 rare
 WASP abnormal
 Hematopoetic cells have abnormal shape, size, fxn
 IgM, failure to respond to polysaccharide vaccines
 hemorrhage
o Phagocytic deficiencies
 Chronic Granulomatous Disease
 Mutation in NADPH oxidase (respiratory burst)
defective killing by macs
 Granuloma formation
 pneumonia, lymphadenitis, abscesses in skin, liver, etc.
 Chediak-Higashi Syndrome
 Neutrophil disorder defective intracellular killing
 Recurrent bacterial infections in lungs, skin, mucous
membranes
 Leukocyte Adhesion Deficiency
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Deficient selectin/ligand on endothelium neutrophils
cannot leave bloodstream
Recurrent infections, impaired healing, lack of pus
formation
Secondary Immunodeficiency Diseases
o More common than primary immune diseases
o Can be caused by:
 Malnutrition
 Aging: B, T cells, innate immunity, tolerance
 Chemotherapeutic agents:
 impacts ALL cells (immunosuppression) especially rapidly dividing cells
 treatment: transfusions, transplantations,
immunotherapy
 Alcohol:
 triggers Cortociotrophin releasing hormone 
glucocorticoids downregulates phagocytes, B,T cells
 Reduces estrogen levels, reduce cytokine production
 Infections
 AIDS