Lect 8 Transplantation & Autoimmunity
Immunosuppression, transplantation: •Acute rejection in a kidney graft is mediated by
- T lymphocytes.
Autoimmune diseases of endocrine glands: adrenal gland
-Addison's disease
Immunosuppression, transplantation: •Mab anti-CD25
-Anti-CD25 monoclonal antibody (basiliximab) -binds IL-2Ra chain, blocks binding of IL-2 to high affinity IL-2R receptor.
Transplantation
-Blood transfusion -Transplantation of solid organs -Suppression before transplantation -Hematopoietic cell transplantation
Autoimmune diseases of endocrine glands: thyroid
-Hashimoto's throiditis -Graves' -subacute thyroiditis -idiopathic hypothyroidism
Immunosuppression, transplantation: •Cytotoxic drugs
-azathioprine, mycophenolate mofetil, cyclophosphamide -block DNA synthesis and cellular proliferation.
Common gut bacteria
-bear antigens similar to A and B antigens -elicit the production of antibodies in individuals that do not have the same antigen on their erythrocytes.
Immunosuppression, transplantation: •Corticosteroids
-block production of inflammatory factors at transcriptional level
Immunosuppression, transplantation: •Cyclosporin:cyclophylin, & tacrolimus:FKBP complexes
-block the activity of calcineurin and T cell activation.
Immunosuppression, transplantation: •Balatacept
-blocks T-cell co-stimulatory signal.
Immunosuppression, transplantation: •Serum sickness
-caused by deposition of immune complexes (in small blood vessels) -and activation of the complement system.
Immunosuppression, transplantation: •Anti-CD52
-causes a depletion of lymphocytes and monocytes
AB0 antigens
-family of glycolipids, at the erythrocyte surface -composed of core structure (lipid ceramide, attached to oligosaccharide consisting of 5 components Glu-Gal-GalNAc-Gal-Fuc) -RBCs of the 0 type only express the core structure at their surface -RBCs of the A type express the A antigen that consists of the core structure with an additional GalNac -RBCs of the B type express the B antigen that consists of the core antigen and an additional Gal -RBCs of the AB type express both A and B antigens.
Blood Transfusion
-form of cell transplantation (donors to recipients)
Blood transfusion in mismatched donors and recipients
-have preformed Abs to donor blood group Ags -results rapid transfusion RXNs -similar to Type II hypersensitivity RXNs
hematopoietic cell transplantation: HLA match, donor, recipient
-important for successful hem-transplant
Immunosuppression, transplantation: •Prednisolone
-is 4 times more anti-inflammatory than prednisone
hematopoietic cell transplantation: • after HC-transplant
-patient attacked by alloreactive T cells in the graft (GVHD)
Transplantation: general
-replacement of cells, tissues, organs -diseased, damaged, worn out *knowledge of immune system: -ability to discriminate between self, non-self
hematopoietic cell transplantation: • bone marrow transplantation
-therapy for geneatic and malignant diseases of hematopoietic cells -chemotherapy, irradiation kill the diseased cells -infusion follows heamatopoietic stem cells from HLA-matched healthy donor
hematopoietic cell transplantation: minor histocompatibility antigens
-trigger alloreactive TCs in recipients HLA-identical transplants
Autoimmune diseases of endocrine glands: islets of Langerhans (pancreas)
-type 1 diabetes (insulin-depend diabetes, juvenile-onset diabetes) -type 2 diabetes (insulin-resistant diabetes, adult-onset diabetes)
hematopoietic cell transplantation: dizygotic twins
-who have had common blood circulationi during gestation are tolerant of each other's tissues
Pemphigus foliaceus is a skin blistering disease caused by autoantibodies specific for desmoglein.
An adhesion molecule in the cell junctions that hold keratinocytes together, desmoglein is a cell-surface protein with five extracellular domains (EC1-EC5). The autoimmune response starts by making harmless antibodies against the EC5 domain; over time, the response can spread to make antibodies against the EC1 and EC2 domains. These antibodies cause disease and are of the IgG4 isotype.
Autoimmune diseases
Autoimmune diseases are classified as types II, III, and IV due to similarities in tissue damages caused by hypersensitivity reactions of the same types: type II is mediated by autoantibodies, type III is mediated by immune complexes, and type IV is mediated by cells of the adaptive as well as cells of the innate immunity. A list of the autoimmune diseases covered in this lecture is provided in the next slide
The effects of treatment of rheumatoid arthritis with anti-TNF-α.
For each parameter measured (level of C-reactive protein, swollen joints, and pain), the values for patients given a placebo treatment are depicted by the blue curve and the values for patients treated with anti-TNF-α antibody are depicted by the red curve.
The characteristic facial rash of systemic lupus erythematosus.
Historically, this butterfly-shaped rash was first used to define and diagnose the disease. Now that the disease is defined immunologically, it is recognized that a proportion of patients who have the disease do not get the rash. Photograph courtesy of M. Walport.
Autoantibodies against the acetylcholine receptor cause myasthenia gravis.
In a healthy neuromuscular junction, signals generated in nerves cause the release of acetylcholine, which binds to the acetylcholine receptors of the muscle cells, causing an inflow of sodium ions that indirectly causes muscle contraction (upper panel). In patients with myasthenia gravis, autoantibodies specific for the acetylcholine receptor reduce the number of receptors on the muscle-cell surface by binding to the receptors and causing their endocytosis and degradation (lower panel). Consequently, the efficiency of the neuromuscular junction is reduced, which is manifested as muscle weakening.
Hashimoto's thyroiditis
In a healthy thyroid gland, the epithelial cells form spherical follicles containing thyroglobulin (panel a). In patients with Hashimoto's thyroiditis the thyroid gland becomes infiltrated with lymphocytes, which destroy the normal architecture of the thyroid gland and can become organized into structures resembling secondary lymphoid tissue (panel b), as shown in the schematic diagram at the right. Micrographs courtesy of Yasodha Natkunam.
The mechanism of celiac disease.
In celiac disease, inflammation of the small intestine is caused by a CD4 T-cell response. The T cells are specific for gluten-derived peptides that have been deaminated by tissue transaminase and presented by HLA-DQ8 or HLA-DQ2 molecules. Only part of the peptide epitope is shown. DC, dendritic cell.
In systemic lupus erythematosus (SLE) the immune response is broadened in a antigen-specific manner
In patients with SLE, an ever-broadening immune response is made against nucleoprotein antigens such as nucleosomes, which consist of histones and DNA and are released from dying and disintegrating cells. The left panel shows how the emergence of a single clone of autoreactive CD4 T cells can lead to a diverse B-cell response to nucleosome components. The T cell in the center is specific for a specific peptide (red circles) from the linker histone H1, which is present on the surface of the nucleosome. The B cells at the top are specific for epitopes on the surface of a nucleosome, on H1 and DNA, respectively, and thus bind and endocytose intact nucleosomes, process the constituents, and present the H1 peptide to the helper T cell. Such B cells will be activated to make antibodies, which in the case of the DNA-specific B cell will be anti-DNA antibodies. The B cell at the bottom right is specific for an epitope on histone H2, which is hidden inside the intact nucleosome and is thus inaccessible to the B-cell receptor. This B cell does not bind the nucleosome and does not become activated by the H1-specific helper T cell. A B cell specific for another type of nucleoprotein particle, the ribosome (which is composed of RNA and specific ribosomal proteins), will not bind nucleosomes (bottom left) and will not be activated by the T cell. In reality, a T cell interacts with one B cell at a time, but different members of the same T-cell clone will interact with the B cells of different specificity. The right panel shows the broadening of the T-cell response to the nucleosome. The H1-specific B cell in the center has processed an intact nucleosome and is presenting a variety of nucleosome-derived peptide antigens on its MHC class II molecules. This B cell can activate a T cell specific for any of these peptide antigens, which will include those from the internal histones H2, H3, and H4 as well as those from H1. This H1-specific B cell will not activate T cells specific for peptide antigens of ribosomes, because ribosomes do not contain histones.
16.19 How antibodies against desmoglein cause skin blistering.
In the early phase of the autoimmune response to desmoglein, antibodies are made against epitopes of the EC5 domain. These epitopes are not accessible to antibody in functional membrane-associated desmoglein, but the antibodies can bind to soluble degradation products of desmoglein (left panel). Soluble immune complexes of antibody desmoglein are bound and processed by B cells specific for epitopes of the EC1 and EC2 domains (center panel). This causes epitope spreading in the later phase of the autoimmune response and the synthesis of high-affinity IgG4 antibodies specific for the EC1 and EC2 epitopes. These epitopes of membrane-associated desmoglein are accessible to antibody, which interferes with the physiological adhesive interactions of desmoglein that are necessary for maintaining skin integrity. Consequently, the antibodies cause the outer layers of the skin to separate, giving blisters (right panel).
Comparison of healthy and celiac intestinal mucosa.
Left: the surface of the normal small intestine is folded into finger-like villi, which provide an extensive surface for nutrient absorption. Right: in celiac disease the inflammation and immune response damage the villi. There is lengthening and increased cell division in the underlying crypts to produce new epithelial cells. There are greater numbers of lymphocytes in the epithelial layer and an increase in effector CD4 T cells, plasma cells, and macrophages in the lamina propria. The damage to the villi reduces the person's ability to utilize food and can cause life-threatening malabsorption and diarrhea. Right photograph courtesy of Allan Mowat.
Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes
Panel a is a micrograph of healthy human pancreas, showing a single islet. The islet is the discrete light-staining area in the center of the photograph. It is composed of hormone-producing cells, including the β cells that produce insulin. Panel b shows a micrograph of an islet from a patient with acute onset of type 1 diabetes. The islet shows insulitis, an infiltration of lymphocytes from the islet periphery toward the center. The lymphocytes are the clusters of cells with darkly staining nuclei. Both tissue sections are stained with hematoxylin and eosin.
Deposition of immune complexes in the kidney glomeruli in systemic lupus erythematosus (SLE)
Panel a shows a section through a glomerulus of a patient with SLE. Deposition of immune complexes causes thickening of the basement membrane. In panel b a similar kidney section is stained with fluorescent anti-immunoglobulin antibodies, revealing the presence of immunoglobulin in the basement membrane deposits. Panel c is an electron micrograph of part of a glomerulus. Dense protein deposits are seen between the glomerular basement membrane and the renal epithelial cells. Neutrophils (N) are also present, attracted by the deposited immune complexes. Photographs courtesy of H.T. Cook and M. Kashgarian.
16.30 Antibodies against streptococcal cell-wall antigens cross-react with antigens on heart tissue.
The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies (yellow) cross-react with the heart, whereas others (blue) do not. An epitope in the heart (orange) is structurally similar, but not identical, to a bacterial epitope (red).
Which of the following describes myasthenia gravis?
The neuromuscular junction is compromised
Autoimmune diseases, which are classified on the basis of the effector mechanism that causes the symptoms, include all of the following types of hypersensitivity reaction except______________.
Type I
The risk of__________________is the primary complication in bone marrow transplants.
acute graft-versus-host disease
The term______________is used to describe polymorphic antigens that vary between individuals of the same species.
alloantigens
Hematopoietic stem cell transplantation is appropriate for all of the following conditions except_______________.
cirrhosis of the liver
Alloantibodies to blood vessel endothelium on solid organ grafts cause ____________ .
hyperacute rejection
The reason why babies born to mothers with Graves' disease suffer passively from the disease for only a short while after birth is that_________________.
only antibodies, and not the B cells making the autoantibodies, cross the placenta
The formation of ectopic lymphoid tissues occurs in all of the following conditions except________________.
pemphigus foliaceus
__________________is a highly variable type III autoimmune disease in which immune complexes form and may cause glomerulonephritis of the kidney, arthritis of the joints, and vasculitis of the face.
systemic lupus erythematosus
Autologous bone marrow transplantation used to treat cancer patients involves reinfusing a(n)________________-depleted stem-cell population into the patient after their cancer treatment has been completed.
tumor cell
ABO blood group antigen structures
•ABO antigens: -glycolipids, erythrocyte surface •core structure: -lipid ceramide -attached oligosaccharide (glucose (Glu), galactose (Gal), N-acetyl galactosamine (GalNAc), galactose, and fucose (Fuc)) *blood group O glycolipid •blood group A: -enzyme + N-acetyl galactosamine (A Ag) •blood group B: -enzyme + galactose (B Ag) •blood groups AB: -express A, B, and core structure alone -reason alloantibodies against O not made
Diseases mediated by antibodies against cell-surface receptors: agonists (stimulate)
•Abs act as agonists when: (stimulate receptor on binding it) •Graves', thyroid stimulating hor receptor, hyperthyroidism (thyroid epith-cell) •hypoglycemia, insulin rec, hypoglycemia (all cells)
Diseases mediated by antibodies against cell-surface receptors: antagonists (block function)
•Abs act as antagonists when: (block receptor's function on binding it) -Myasthenia gravis, acetylcholine rec, progressive muscle weakness (muscle) -insulin-resistant diabetes, insulin rec, hyperglycemia, ketoacidosis (all cells)
donor, recipient of bone marrow transplant: share HLA class I, II to reconstitute TC function in recipient
•After BM-transplantation: -donor-derived thymocytes positively selected on HLA mol.s carried by recipient's thymic epithelium •hypothetical situation, none of recipient's HLA allotypes are same as donor's HLA allotypes: -recipient could not reconstitute TC system -suffer severe combined immunodeficiency •hypothetical situation, recipient & donor share HLA allotypes: •clinical practice, BM-transplant donors & recipients chosen to share as many HLA class I, II allotypes as possible *APC, antigen-presenting cell
Graft-versus-host disease: donor TCs (graft) attack recipient's tissues
•After BM-transplantation: -mature donor CD4, CD8 TCs (in graft) specific for recipient's HLA allotypes, activated in 2ºLT -effector CD4, CD8 TCs move to circulation -preferentially enter, attack tissues most damaged by chemotherapy, irradiation (skin, intestines, liver)
Autoimmunity
•Autoimmune disease: -resembles type II, III, IV hypersensitivity reaction -arise when tolerance to self antigens is lost -HLA is the dominant genetic factor affecting susceptibility to autoimmune diseases -HLA association reflects the importance of T cell tolerance in preventing autoimmunity •Autoimmune diseases caused by autoantibodies
chemical structures, metabolism of cytotoxic drugs
•Azathioprine: -modified anticancer drug 6-mercaptopurine -blocks reactive thiol -metabolism slowed, converted to 6-mercaptopurine (in-vivo), then metabolized to 6-thioinosinic acid -blocks pathway of purine bio-SYN •Mycophenolate (newer drug): -also blocks purine bio-SYN after being metabolized to mycophenolic acid •Cyclophosphamide: -stable pro-drug -activated enzymatically (in body) -to phosphoramide mustard (strong, unstable DNA-alkylating agent) •Methotrexate: -blocks DNA SYN, interferes w/thymidine SYN
Inhibition T-cell co-stimulation by soluble CTLA4
•Belatacept, soluble chimeric protein: -combines extracellular domain CTLA4 -to hinge, Fc domains of IgG1 HC •belatacept, mutations (m): -made in CTLA4 part, to INV avidity for B7 -made in hinge, eliminate Fc-mediated effector function *Belatacept does not interfere: -w/ alloreactive TC recognition foreign MHC (on transplanted tissue) *Belatacept does interfere: -binding tightly to B7 -prevents CD28 from B7, 2nd signal (activates naive alloreactive TCs)
mixed lymphocyte RXN: cellular test HLA difference (transplant donor, recipient, potential graft rejection) alloreactive response, TC cytotoxicity
•Blood lymphocytes, monocytes, DCs: -isolated from patient (recipient kidney graft) -isolated from kidney donor (cells irradiated) •donor's irradiated cells: -act as stimulators, not responders •patient + donor cells cultured together (5 days): -alloreactive TCs (patient) activated by allogeneic HLA I/ II molecules (donor) -prolif/differentiation TCs measured (4 days) -capacity of effector CD8 TCs to kill donor cells cultured (5 days) *Proliferation measures magnitude alloreactive response *Killing of donor cells measures capacity graft rejection (TC cytotoxicity)
Inhibition alloreactive T-cell activation by monoclonal CD25-specific antibody (chimeric basiliximab, humanized daclizumab)
•CD25: -not part low affinity IL-2R naive alloreactive TCs -is α chain high-affinity IL-2R alloreactive TCs (TCs activated by signals 1, 2) •high-affinity IL-2R:anti-CD25 -prevents IL-2 binding to receptor -prevents signal 3 -interferes activation, prolif, different TCs •Anti-CD25 antibodies: -clinically, chimeric basiliximab, humanized daclizumab
Acute rejection kidney graft: direct pathway allorecognition
•CD8 TCs respond to HLA class I differences •CD4 TCs respond to HLA class II differences •Donor dendritic cells (in graft): -carry complexes donor HLA mol.s, peptides -DCs travel to spleen, move to TC areas -recipient's alloreactive T lymphocytes activated -effector TCs travel (blood) to grafted organ -attack cells express complexes peptide, HLA I/II (recognized by their T-cell receptors)
Effects of corticosteroids on immune system (anti-inflammatory effects)
•Corticosteroid therapy: -alters expression of many genes -to achieve anti-inflammatory effects •REDuce production inflammatory mediators: -cytokines, prostaglandins, nitric oxide (NO) •DEC SYN IL-2 (of activ-lymphocytes) from their effects on other cytokines •prevent inflammatory cell migration: -by inhibiting expression of adhesion mol.s • promote apoptotic death (leukocytes, lymphocytes)(endonucleases) *NOS, nitric oxide synthase
Steroids change patterns of gene transcription
•Corticosteroids: -lipid-soluble, diffuse PM -bind receptors in cytosol •Binding (corticosteroid-receptor) -displaces heat-shock protein (Hsp90) -exposes DNA-binding region (of receptor) -enters nucleus, binds specific DNA seqs (promoter region, steroid-responsive genes) *Corticosteroids modulate transcription: -variety of genes
Direct, indirect pathways allorecognition: graft rejection
•DCs from organ graft stimulate: -direct, indirect pathways allorecognition (travel from graft-draining lymphoid tissue) •allogeneic HLA I, II allotypes (donor DC): -interact dircetly w/ TCR receptors (recipient's alloreactive CD4, CD8 TCs) *direct allorecognition •death of same APC produces mem-vesicles: -contain allogeneic HLA I, II allotypes -endocytosed (by recipient's DCs) -peptides (donor's HLA) presented (by recipient's HLA mol.s) to peptide-specific TCs *indirect allorecognition •HLA II presentation to CD4 T cells •donor derived HLA peptides (presented by recipient HLA I mol.s to CD8 TCs)
Three mechanisms destroy erythrocytes in autoimmune hemolytic anemia
•Erythrocytes opsonized with IgG: -bound, engulfed by phagocytes (spleen) •phagocytes (spleen) bear (one/both): -Fcγ receptor -complement receptor (CR1-expressing cells) •complement fixation (erythrocyte surface)\- -complem-mediated lysis (opsoniz erythrocyt)
Transplantation of solid organs
•Matching donor + recipient HLA class I and class II : -improves success of transplantation -Tissue mapping (donors, recipients) performed by mixed lymphocyte reaction.
Temporary symptoms of antibody-mediated autoimmune diseases, passed from affected mothers to newborns
•Mother (Graves') makes anti-TSH Abs: -ophthalmopathy causes eyes to bulge -IgG autoantibodies agains thyroid-stimulating hormone receptor (TSHR) pass mother to fetus (utero) -passively give baby temporary Graves' disease (disappears w/ degradation maternal IgG (infant's circulation))
blood transfusion: matching ABO, Rhesus D (RhD) erythrocyte antigens
•O represents the absence of both A, B Ags •O RhD−: -lack all 3 antigens (A, B, Rhesus D) -universal donors -receive blood only from O RhD− •AB RhD+ all 3 antigens: -universal recipients -donate only to AB RhD+ *frequency of eight blood types US pop
need for tissue transplants outruns supply of donated organs:
•Patients eligible for transplant: -wait 2−3 years US/UK •waiting patients (US) 1999−2008 : -2007, 28,353 transplants performed -Ea yr 6000+ patients die b/4 receive transplant
Chemical structures: hydrocortisone, prednisone, prednisolone
•Prednisone: -SYN-analog adrenocorticosteroid hydrocortisone/ cortisol -converted in vivo active form, prednisolone -1,2 =bond into A ring prednisone) -INC anti-inflammatory by 4x (compared to hydrocortisone)
Chronic rejection; hypersensitivity RXN type III
•Production anti HLA I & II antibodies by B cell: -mediated by activation of CD4 T cell -by the indirect pathway of allorecognition -results in deposits of HLA Ags, & anti-HLA Abs -in blood vessels of organ transplant -similar to hypersensitivity reaction type III •Presentation of donor antigens by recipient DCs -by indirect pathway of allorecogition -causes chronic graft rejection
targets for immunosuppressive drugs (organ transplant): act at diff stages in activation alloreactive TCs
•Rabbit anti-thymocyte globulin (rATG), anti-CD52 monoclonal Ab (alemtuzumab): -depletes TCs, leukocytes (immuno-depletion) -before transplantation •Anti-CD3 monoclonal antibody (mAb): -prevents signal 1 from α:βTCR-CD3 complex -as DC Agp:MHC interacts w/ TCR complex •cyclosporin & tacrolimus: -interfere with delivery of signal 1 -inhibit action of calcineurin (Ca2+) -prevents NF-AT, IL-2 transcription •CTLA4:Fc fusion protein belatacept: -binds B7 (DC), prevents signal 2 (CD28 co-stim Rec of T cell) •anti-CD25 antibody (Basiliximab): -binds high-affinity IL-2R (partly act TC) -prevents signal 3, mTOR, Cyclin/CDK •Sirolimus: -interferes delivery of signal 3 -mTOR, Cyclin/ CDK •Azathioprine, mycophenolate, methotrexate, cyclophosphamide: -sabotage replication, prolif. activated TCs (interferes w/ DNA replication)
Minor histocompatibility antigens: peptides derived from polymorphic proteins, other than HLA I, II mol.s
•Self proteins routinely digested by proteasomes (cytosol) •peptides derived delivered to ER: -bind MHC I, delivered cell surface •a polymorphic protein that differs btwn graft donor & recipient: -can give rise to antigenic peptide -recognized by recipient's TCs as non-self -elicit IR (minor histocompatibility antigens)
Cyclosporin, tacrolimus: inhibit T-cell activation (by interfering serine/threonine phosphatase calcineurin)
•Signaling via T-cell receptor-ass tyrosine kinases: -activates transcription factor AP-1 -Ca2+ binds calcineurin -activates by -Pi cytoplasmic form (of nuclear factor activated TCs (NFAT)) -dephosphorylated, active NFAT: -migrates to nucleus, complexes w/ AP-1 •NFAT:AP-1 complex induces transcription: -of genes required for T-cell activation -including gene encoding IL-2 •Cyclosporin & tacrolimus: -interfere w/activation of AP-1 -Cyclosporin:cyclophilin -tacrolimus:FK-binding protein (FKBP) -Cyclosporin:cyclophilin:calcineurin (blocks its ability to activate NFA) -tacrolimus:FKBP:calcineurin (at same site, also blocking its activity)
cyclosporin, tacrolimus: Immunological effects
•T lymphocyte •B lymphocyte •Granulocyte
Autoantibodies against TSH receptor: cause overproduction of thyroid hormones and Graves' disease
•Thyroid epithelial cells : -make thyroglobulin (glycoprotein) -stored follicles, spherical arrangement of thyroid cells -Iodide taken up, iodinates/ cross-link tyrosine residues of thyroglobulin •when thyroid hormones are needed: -Thyroid-stimulating hormone (TSH, pituitary) -binds TSH receptor (thyroid cells) -induces endocytosis, breakdown iodinated thyroglobulin -release triiodothyronine (T3), thyroxine (T4) •T3, T4: -regulate metabolism -signal pituitary to stop release TSH *Graves' disease, auto-Abs bind TSH receptor (thyroid cells), micmic TSH: -stimulation by anti-TSH receptor antibody causes Graves' -induce continuous SYN, release thyroid hormones -production independent of presence of TSH
success of hematopoietic cell transplantation correlates with extent of HLA match
•Two parameters of clinical outcome: -survival of patient -incidence of severe graft-versus-host GVHD •Severe GVHD, grades III, IV •allele match (donor, recipient): -identical HLA-A, -B, -C, -DR alleles •single mismatch: -donor & recipient differ by 1 HLA I/ II allele •Transplants (class I, II mismatch): -have one mismatched allele (each, HLA I, II) -the fewer the mismatches, the better the survival, health of transplanted patient
HLA matching: improves survival transplanted kidneys
•actual (5 years), projected survival rates kidney grafts: -patients with HLA mismatches no (blue), 1 (orange), 2 (red), 3 (dark blue), 4 (green), 5 (black), 6 (brown) (semi-log scale)
Disruption of Healthy Tissue by Adaptive Immune Response
•autoimmune diseases (symptoms, autoantigens associated w/ IR): -types II, III, IV (by tissue-damaging effects) -similar to hypersensitivity RXNS II, III, IV •snRNP, small nuclear ribonucleoprotein: •scRNP, small cytoplasmic ribonucleoprotein
Dystrophic fingernails: APECED
•autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: -genetic autoimmune disease -hypoparathyroidism, underfunction of parathyroid glands (control Ca2+) -candidiasis (yeast infection) -adrenal insufficiency (underfunction of adrenal gland)
Transplantation solid organs: Hyperacute rejection, type II hypersensitivity reaction, caused by preexisting antibodies binding to the graft
•before transplantation recipient Abs: -could react w/donor ABO/ HLA class I Ags •donor organ grafted into recipient: -Abs immediately bind vascular endothelium -initiate complement, clotting cascades -graft-blood vessels obstruct (clots, leak) -hemorrhage of blood into graft -graft purple from deoxygenated blood, dies *hematopoietic cell transplant, ABO compatibility not required
Chronic rejection kidney transplant, immune complexes deposited in blood vessel walls (transplant)
•chronic rejection caused by: -complexes HLA, anti-HLA Abs deposit in BV •Immune complexes (endothelial cells): -recruit Fc receptor (monocytes, neutrophils) -internal elastic lamina, smooth muscle cells -internal elastic lamina thickening (damage) -infiltration SM cells, macrophages, granulocytes, alloreactive TCs, Abs -BV-lumen narrows, chronic inflammation -intensifies tissue repair -BV becomes obstructed, ischemic, fibrotic
Immunosuppressive methods prevent transplant rejection: Anti-CD52, depletes leukocytes
•depletes leukocytes transplant patients : -Anti-CD52 fixes complement (leukocyte surface, consigns to phagocytosis) -CD52 small, MW 8 kDa (160 kDa IgG, 180 kDa C3b) •bound CD52: -anti-CD52 brought close to cell surface -INC C3b covalent binding (leukocyte)
successful corneal allograft
•from cadaveric donors requires no HLA assessment: -no administration of immunosuppressive drugs •lack of any rejection response: -due to naturally immunosuppressive env in eye -anterior chamber lacks blood vessels in cornea
blood transfusion: donors, recipients matched, ABO system blood group antigens
•gut bacteria bear antigens resemble the blood group A and B antigens: -individuals lack A-/B-/both-blood group Ags -bacterial Ags stimulate Ab response against •type O: -lack A, B, have anti-A, anti-B Abs •type AB : -have neither *combinations result immune RXN (red)
Serum sickness: type III hypersensitivity RXN
•intravenous (high dose) •subcutaneous •inhaled
Clinical transplantation
•involves: -donated organ +transplant recipient (stressed and inflamed)
Acute rejection in kidney graft:
•lymphocytes around kidney arteriole (A) undergoing rejection: •lymphocytes surrounding renal tubules (T) •T lymphocytes with anti-CD3
Pregnancy: natural situation that leads to production of anti-HLA antibodies
•mother and father (human families): -have different HLA types -fetus, pregnant motherexpresses HLA haplotype maternal, paternal origins -fetal, paternal HLA class I, II mol.s alloantigens -protected from mother's immune response during pregnancy (from preexisting alloreactive antibodies/TCs) -birth, fetal cells, Ags enter maternal circulation, stimulate adaptive IR
indirect pathway of allorecognition: stimulates production anti-HLA Abs, cause chronic graft rejection
•process/present allogeneic HLA I (by recipient DC): -recipient DC activates helper CD4 TCs -activate BCs (bound, internalized allogeneic donor HLA) •cognate interaction leads to anti-HLA I Ab: -anti-HLA II Abs produced similarly •activae-endothelium expresses HLA I, II Abs: -Abs against HLA I, II result chronic rejection
Erythrocytes
•red blood cells (RBCs): -differ in blood group antigens -most important in blood transfusion are A, B, 0, RhD -Donors, recipients (blood transfusion) matched for compatibility (AB0 and RhD antigen)
Gross appearance: acutely rejected kidney
•rejected graft: -swollen, deep-red areas (hemorrhage) -gray areas (necrotic tissue)
Alloreactions transplant rejection, graft-versus-host reaction
•rejection of transplanted organ: -when recipient makes IR against transplant -TCs attack transplant •Graft-versus-host disease: -hematopoietic cells transplanted (BM) -TCs bone marrow attack recipient's tissues (skin, liver, intestines)
Autoantibodies specific for type IV collagen react w/ basement membranes of kidney glomeruli: Goodpasture's syndrome
•renal corpuscle (Goodpasture's syndrome): -glomerulus IgG deposition (immunofluorescence) -Ab against glomerular BM deposited linearly •autoantibody causes local activation cells bear Fc receptors: -activation of complement -influx of neutrophils •hematoxylin, eosin stain renal corpuscle: -glomerulus compressed -by proliferating mononuclear cells (Bowman's capsule) -influx of neutrophils into glomerular tuft
Acute rejection; hypersensitivity type IV
•similar to hypersensitivity type IV: -involves alloreactive CD4 and CD8 cells •Acute rejection by direct allorecognition: -involves donor antigen presentation by donor DCs to the recipient •Acute rejection of organ by transplantation of an organ from a dead donor into an inflamed recipient:
Hyperacute rejection; type II hypersensitivity RXN
•similar to type II hypersensitivity reactions: -occurs when recipient has preexisting antibodies to donor blood group antigens or to HLA I, HLA class II.
Dizygotic twins: common blood circulation (gestation), tolerant of each other's tissues, MLRs
•stimulation index, derived from: -results mixed lymphocyte RXNs (MLRs) •MLRs: -lymphocytes of ea twin stimulated by other twin, & an unrelated control -when lymphocytes used as stimulators in MLR against the other's, & vice versa, a negligible response is obtained, compared to a strong response that both make to lymphocytes from an unrelated control
Immune-complex disease (type III)
•subacute bacterial endocarditis: -bacterial Ag, glomerulonephritis •mixed essential cryoglobulinemia: -rheumatoid factor IgG complexes (w/w-out hepatitis C Ags), systemic vasculitis •systemic lupus erythematosus: -DNA, histones, ribosomes, snRNP, scRNP (sm nuclear, cytoplasmic ribonucleoprotein) -glomerulonephritis, vasculitis, arthritis
Hematopoietic Cell Transplantation: Bone marrow transplantation
•therapy genetic, malignant diseases of hematopoietic cells: -patient's diseased hematopoietic system destroyed by chemotherapy, irradiation -infusion hematopoietic stem cells -from healthy HLA-matched donor -Over months, hematopoietic stem cells (graft) reconstitute patient w/ healthy hematopoietic system
T-cell mediated disease (type IV)
•type 1 diabetes (insulin-dep diabetes mellitus): -pancreatic β-cell Ag, β-cell destruction rheumatoid arthritis: -unknown synovial joint Ag, joint inflammation, destruction •multiple sclerosis: -myelin basic protein, proteolipid protein, brain degeneration, paralysis
