Week 5 Flashcards
The end of the immune response
• At the end of an immune response, reduced antigen exposure results in a reduced expression of IL-2 and its receptor. (In response to IL-2, cells will continue to grow and divide and fight off infection—Response dwindles without IL-2 present). IL-2 production is a result of the CD28-B7 interaction. Recall CD25 is the high affinity IL-2 receptor. The interaction between CTLA-4 and CD 80/86→that also starts to result in the down regulation of IL-2 and its receptor. This is a timed interaction that can be stimulated by the presence of Treg cells.
o This leads to apoptosis of the antigen-specific T cells.
o The majority of antigen-specific cells die at the end of an immune response.
o A small population of long-lived T and B cells survive and give rise to the memory population.
CCR7
CCR7 is important in trafficking to the lymph node
• Several molecules have been identified to be necessary for tolerogenic DC: T cell interactions.
o These include surface molecules such as E-cadherin, PD-1 L, CD103, CD152 (CTLA-4) and ICOS-L (CD275) and cytokines, including IL-10 and TGF-β.
• T reg cells have a 4-fold process:
• T reg cells have a 4-fold process: Cytokine production (IL-10—suppresses TH1 growth, TGF-beta—strong inhibitory growth signal, IL-35—an auto-inducer of Treg cells). If a B cell is around—IL-10 plus TGF beta can actually cause a class switch recombination to IgA. So Treg also provide instructions to B cells! T reg cells can also soak up remaining amounts of IL-2 that are produced in periphery. 3rd: Cell-mediated cytotoxicity-like event where they can kill effector T cell populations via granzymes.
Lupus
Systemic Lupus Erythematosis
• Involves multiple organs, characterized by the formation of multiple autoantibodies, particularly anti-nuclear antibodies (ANA’s), in which injury is caused mainly by deposition of immune complexes and binding of Ab to various cells and tissues
• Onset of DZ may be acute or chronic – typically a chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney, and serosal membranes (although virtually any organ system can be affected)
• Prevalence: 1 in 2500 in certain populations – relatively common
• Hallmark of SLE: production of autoantibodies – play a major role in the pathogenesis of the disorder, and measurement of these autoantibodies have value in the diagnosis and management of patients with SLE
• Patients have a variety of ANAs – can be detected by immunoassay (ANA test) and indirect immunofluorescence
o Pattern of nuclear fluorescence suggests the type of anti-nuclear antibody present
o Immunofluorescence test of for ANA’s has largely been replaced by immunoassay tests for specific nuclear antigens
o In SLE, antibodies for double stranded DNA and Smith (Sm) antigen are virtually diagnostic for SLE
o Most of the systemic lesions of SLE are caused by immune complex deposition (type III hypersensitivity)
• In addition to ANAs, patients with SLE can have antibodies directed against red cells, platelets, & white cells
o AutoAb opsonize cells & promote their phagocytosis and lysis→ cytopenias = Ab mediated (type II) hypersensitivity
• Patients with SLE may also have autoantibodies that react with proteins complexed with phosopholipids (30-40% of patients)
o Anti-phospholipid Ab may produce false + syphilis test & can prolong partial thromboplastin time (lupus anticoagulant)
o Despite having in vitro anticoagulant activity, anti-phospholipid Ab are associated with complications of a hypercoagulable state → pts can get venous & arterial thrombosis → spontaneous miscarriages & cerebral ischemia
• Aka secondary anti-phospholipid antibody syndrome, as it is occurring in association with SLE
• Fundamental defect = failure of mechanisms to maintain self-tolerance
o Related to the presence of susceptibility genes coupled with environmental triggers
• Ex. exposure to UV light, estrogen, certain medications)
o Environmental triggers →apoptosis and increased burden of nuclear Ag in a genetically susceptible individual
o Loss of self-tolerance and persistence of nuclear Ag → formation of Ag-Ab complexes→ deposited in tissues → injury
• Primarily an immune complex-mediated disease, type III hypersensitivity
• The pathologic features of SLE are widespread and quite variable!
• Susceptibility genes interfere with the maintenance of self-tolerance and external triggers lead to persistence of nuclear Ag
o Result = Ab response against self nuclear Ag, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type 1 IFNs
o Neutrophil Extracellular Traps (NETs) = neutrophils release their nuclear material forming fibril traps to limit spread of infectious agents – the released nuclear chromatin is a source of nuclear antigens
• Pathologic findings:
o Acute necrotizing vasculitis – can affect virtually any organ
o Kidney (lupus nephritis) – due to immune complex deposition in the glomeruli, tubular, or peritubular capillary basement membranes, or larger blood vessels → a variety of patterns of glomerular injury are seen
• Lupus nephritis: glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes is seen
• Smooth immunofluorescence (in comparison to Goodpasture – granular)
o Skin: erythema in light exposed areas; typically immune complex deposition at the dermoepidermal junction.
o Joints: non-erosive, non-deforming small joint involvement (in contrast to RA)
o CV: fibrinous pericarditis, non-bacterial verrucous endocarditis; accelerated coronary atherosclerosis in long-term DZ
o Spleen: splenomegaly
o Lungs: pleuritis, pleural effusion, interstitial fibrosis
o SOAP BRAIN MD: serositis, oral ulcers, arthritis, photosensitivity/pulmonary fibrosis, blood cells, renal/Raynauds, ANA, immunologic (anti-Sm, anti-dsDNA), neuropsych, malar rash, discoid rash
• Over 90% of patients with SLE survive for 10 years or more – most common COD is infection due to immunosuppression
• Chronic discoid lupus erythematosis:
a form of SLE predominantly limited to the skin
o Patients have a chronic photosensitive dermatosis w/ atrophy and scarring that can be seen in SLE, but patients do not have the systemic manifestations of classic SLE
o Patients are usually negative for antibodies to double stranded DNA
• Subacute cutaneous lupus erythematosis:
another form of SLE predominantly limited to the skin, but mild systemic lesions may be present – skin findings take a variety of forms, and most patients will have mild systemic SLE symptoms
o There is an association with antibodies to SS-A and HLA-DR3 genotype
• Drug induced lupus erythematosus
certain drugs (procainamide and hydralazine) bind to histones, causing them to be immunogenic → anti-histone antibodies develop → lupus-like syndrome
• ANA can be positive in all of the CT diseases; many medications can give a + ANA test in the absence of disease
o Some 3-4% of disease free individuals can have positive ANA
o Best screening test for SLE = ANA → follow-up + ANA with anti-ds DNA and anti-Sm (Smith) in the dx of SLE
Rheumatoid Arthritis
• Chronic systemic inflammatory disorder that may affect many tissues and organs, but primarily attacks the joints
o Produces a nonsuppurative proliferative and inflammatory synovitis → progresses to destruction of the articular cartilage and ankylosis (stiffening or immobility) of the joints
• Pathogenesis = uncertain – thought to be triggered by exposure to an arthritogenic (arthritis causing) antigen in a genetically predisposed individual that results in a breakdown of immunological self-tolerance and a chronic inflammatory reaction
o Initial arthritis thus leads to a continuing autoimmune reaction – activation of CD4+ helper T-cells & release of inflammatory mediators and cytokines that ultimately destroy the joint
• In addition to a T cell response, there is also a B cell response, producing autoantibodies
o Genetic susceptibility is a major contributor to the disease, with specific HLA alleles and other genes linked to the risk of developing RA (ex. HLA-DRB1, PTPN22)
• Environmental arthritogen(s) are unknown, but many of the autoAb produced are specific for citrullinated peptides (CCPs)
o These peptides are formed when there is post-translational conversion of arginine to citrulline
o CCPs are produced during inflammation – infection and smoking may promote citrullination of self proteins, triggering the autoimmune reactions in genetically susceptible individuals
o Presence of antibodies to cyclic CCPs can be used as a diagnostic test for rheumatoid arthritis
• Citrullinated proteins are implicated as an autoantigen
o Activation of CD4+ T cells & B cells results in formation of a pannus (mass of inflamed synovium) which grows over the joint cartilage and results in inflammatory destruction of the joint
o Autoantibodies include rheumatoid factor (typically IgM autoantibody to Fc portion of IgG) and Ab to citrulline-modified peptides (anti-cyclic citrullinated peptide antibodies, ACCP)
o RF is not specific for RA (1-5% of healthy people); ACCP antibodies appear to be more specific for RA
• Resected subcutaneous RA nodule with area of central fibrinoid necrosis surrounded by a palisade of macrophages and scattered chronic inflammatory cells
Sjogren Syndrome
• Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), resulting from autoimmune, immunologically mediated destruction of the lacrimal glands and salivary glands
o Primary Sjogren Syndrome: can occur as an isolated disease
o Secondary Sjogren Syndrome: in association with another AI disorder (RA [most common association], SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease)
• Disease typically occurs in middle age women
• Pathogenesis = unknown – thought to be related to aberrant T & B cell activation in genetically susceptible individuals
o Possible trigger: viral infection of salivary glands
• Pathology = lymphocytic inflammation involving lacrimal and salivary glands, followed by fibrosis and gland atrophy
o May also see parotid gland enlargement due to inflammation (Mikulicz disease)
o Some patients will exhibit extraglandular DZ, such as synovitis, diffuse pulmonary fibrosis, and peripheral neuropathy
• Patients characteristically have antibodies to ribonucleoproteins SS-A and SS-B (not specific)
• Dx: clinical findings + clinical tests of tear production, tear clearance, and conjunctival damage
o Measurement of the above antibodies and lip biopsy (to assess minor salivary gland inflammation) are also used
• Increased risk for development of lymphoma (typically a marginal zone lymphoma, MALT) – 5% of patients
Systemic Sclerosis (Scleroderma)
• Chronic inflammation, presumably AI in nature, with widespread damage to small blood vessels and progressive interstitial and perivascular fibrosis of the skin and multiple organs – occurs in adults, 3:1 F:M ratio
o Skin most commonly affected, but GI tract, kidneys, heart, muscles, and lungs are also frequently involved
• The disease is clinically heterogeneous, and several subtypes have been described:
o Diffuse: widespread skin involvement at onset, with rapid progression and early visceral involvement
o Limited: skin involvement confined to fingers, forearms, & face, w/ late visceral involvement (more indolent)
• Some patients with the limited form develop ***CREST syndrome = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia
• Cause = unknown, but may be related to an abnormal, autoimmune response by CD4+ T cells to an unknown antigen(s) with release of cytokines that activate inflammatory cells and fibroblasts
o Inappropriate humoral immunity (autoAb) is also involved; progressive fibrosis also seen
o Small vessel (microvascular) damage is also consistently present, along with ischemic damage
o The pathologic findings are secondary to ischemic damage and fibrosis in the affected organs
o Pts may have antibodies to Scl-70 (DNA topoisomerase 1); patients w/ CREST syndrome may have anti-centromere Ab
• Clinical and pathologic findings include:
o Raynaud’s phenomenon (most common initial complaint)
o Skin: sclerotic atrophy & sclerosis (sclerodactyly), beginning in distal fingers & extending proximally (can also be in face)
• Extensive dystrophic calcification in the subcutaneous fat can also be present.
o GI tract: involved in 90% of patients; esophageal fibrosis results in dysmotility, with dysphagia and reflux; small bowel involvement can result in loss of villi and dysmotility with malabsorption, cramps, and diarrhea
o Lungs: interstitial fibrosis (respiratory failure is the most common COD)
o MS: non-destructive arthritis; 10% of pts can develop an inflammatory myositis indistinguishable from polymyositis.
o Kidneys: vascular thickening; patients may develop HTN
• Raynaud’s phenomenon = exaggerated vasospastic response to cold or emotional stress, causing discoloration of the fingers, toes, and occasionally other areas – can last for minutes or hours
o Not unique to scleroderma, and can be seen as an isolated phenomenon or in association with other CT DZs (SLE)
Inflammatory Myopathies: Dermatomyositis
• AI DZ w/ immunologic injury & damage to small blood vessels and capillaries in the skeletal muscle, along with skin involvement and characteristic skin rash
• Muscle biopsy shows lymphocytic inflammation around small blood vessels and in the perimysial connective tissue, along with perifascicular myocyte atrophy secondary to ischemia
• Necrotic muscle fibers with regeneration can also be seen. Activated B and T cells and antibodies with complement activation are involved in the capillary damage.
• Certain autoantibodies are associated with specific clinical features
• Clinical manifestations typically involve muscle weakness and skin rash
o Classic rash = violaceous discoloration of upper eyelids associated with periorbital edema, accompanied by a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules)
o Muscle weakness typically affects proximal muscles first and is symmetric, often accompanied by myalgias
o Extramuscular manifestations may be present = interstitial lung disease, dysphagia secondary to involvement of oropharyngeal and esophageal muscles, and myocarditis
o 15-25% of pts with dermatomyositis have an underlying malignancy (screen newly dx patients for malignancy!)
o Juvenile form of the disease exists, more often is accompanied by abdominal pain and involvement of the GI tract
o Patients will have elevated creatine kinase; treat with immunosuppressive agents
Inflammatory Myopathies: Polymyositis
• Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement
• This disorder is also seen mainly in adults
• AutoAb similar to that seen in dermatomyositis may be present – anti-Jo1, which is directed against histidyl t-RNA synthetase
• Pathogenesis = immunologic injury to muscle by activated CD8+ cytotoxic T cells
o Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without the perifascicular atrophy seen in dermatomyositis
o Necrotic and regenerating muscle fibers are found throughout the fascicle – no vascular injury is seen
• Patients will have elevated creatine kinase; treat with immunosuppressive agents
Mixed Connective Tissue Disease
• 6 main systemic CT (collagen vascular) DZs: SLE, RA, scleroderma, polymyositis, dermatomyositis, secondary Sjogren syndrome
X-linked Agammaglobulinemia (Bruton’s Aggammaglobulinemia)
• Failure of B-cell precursors (pro-B and pre-B cells) to develop into mature B cells
• Due to mutation in an X-linked gene which codes for cytoplasmic TK required for B cell maturation (Bruton tyrosine kinase, Btk)
• Affected ind will have markedly decreased or absent B cells in peripheral blood, decreased or absent Ig, no plasma cells, and underdeveloped germinal centers in lymph nodes and Peyer’s patches – T cell-mediated reactions are normal
• Disease is seen almost entirely in males (X-linked recessive disorder), but sporadic cases have been seen in females (possibly due to other mutations affecting B cell maturation)
o Clinical symptoms do not become apparent until age 6 months, when maternal immunoglobulins become depleted
• Disease susceptibility:
o Recurrent sinopulmonary bacterial infections (pharyngitis, otitis media, bronchitis, and pneumonia) to Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus (failure of opsonization)
o Patients are also susceptible to certain viral infections requiring neutralizing antibodies (enterovirus meningitis) and often have persistent Giardia lamblia infection (no IgA in GI tract)
o As T cell immunity is intact, generally no increased susceptibility to viral, fungal, or protozoal infections
o Paradoxically, these patients are at risk for autoimmune diseases such as arthritis and dermatomyositis
• Tx: administration of prophylactic Ig therapy
Common Variable Immunodeficiency
• Characterized by a failure of B cells to differentiate into plasma cells → decreased Ig production (hypogammaglobulinemia)
• In contrast to X-linked agammaglobulinemia, normal # of B cells are present in the peripheral blood, but they cannot mature to plasma cells (no plasma cells are seen)
o Decrease in gammaglobulins often affects all classes, but sometimes only IgG is reduced
o B cell lymphoid areas (germinal centers) are hyperplastic
• Sporadic & inherited forms of the disease occur – intrinsic B cell defects as well as defects of helper T cell mediated activation of B cells may account for the antibody deficiencies
• Dx: based on exclusion of other well-defined causes of decreased antibody production
• Sx: similar to that seen with X-linked agammaglobulinemia (sinopulmonary bacterial infections, serious enterovirus infection (meningoencephalitis), Giardia), herpesvirus infections are also common
o In contrast to X-linked agammaglobulinemia, both sexes are affected equally and onset of symptoms is later, in childhood or adolescence, or in some cases, young adults
• Tx: administration of prophylactic Ig therapy
• Patients are at risk for AI DZs, and there is an increased risk of lymphoid malignancies, as well as increased risk of gastric cancer
Isolated IgA Deficiency
• Failure of B cells to differentiate into IgA producing plasma cells → serum and secretory IgA levels are decreased
• Disorder may be familial, or acquired as a result of infection (toxoplasmosis, measles, other viral infections)
o In the USA, 1 in 600 individuals of European descent are affected, and most are asymptomatic (80%)
• Sx: mucosal defenses weakened, so increased sinopulmonary infections and diarrhea (due to Giardia) are seen
o Patients with isolated IgA deficiency who also have deficiency of IgG2 and IgG4 subclasses of IgG are particularly prone to developing infections
o Patients have a high frequency of respiratory tract allergies, and have increased risk of AI DZ (esp SLE and RA)
o Some individuals will develop severe, even fatal anaphylactic reactions to transfused blood products (normal IgA in the blood product acts like a foreign antigen).
DiGeorge Syndrome (Thymic Hypoplasia)
• T cell deficiency due to failure of development of the third and fourth pharyngeal pouches
o Normally give rise to the thymus, parathyroid glands, clear cells of the thyroid, and the ultimobranchial body
• Individuals with this syndrome have variable loss of T cell-mediated immunity (thymic hypoplasia or lack of the thymus), tetany (lack of parathyroid glands), congenital defects of the heart and great vessels, and facial abnormalities
o Usually not familial, but due to a sporadic deletion of a gene on chromosome 22q11, which is seen in 90% of affected patients (DiGeorge syndrome = part of 22q11 deletion syndrome)
• Low levels of T lymphocytes in the peripheral blood, and T cell areas in the lymph nodes and spleen are depleted
o Deficiency in cell-mediated immunity makes individuals susceptible to fungal, viral, and Pneumocytis jiroveci infections
o Serum Ig levels may be normal or reduced, depending on the severity of the T cell deficiency
Hyper IgM Syndrome
• Patients are able to make IgM but are deficient in their ability to make IgG, IgA, and IgE antibodies (defect in immunoglobulin class switching, failure of B cells to switch from IgM to other classes of immunoglobulins)
o Normal to elevated IgM, no IgA or IgE, and very low levels of IgG – normal # of T (60-70%) and B (10-20%) cells
• Molecular defect(s) affects the ability of CD4+ T helper cells to deliver activating signals to B cells and macrophages, which is necessary for class switching – T cells need to express CD40L for this to occur
o Approximately 70% of individuals have X-linked recessive mutations in the gene encoding CD40L
o Other individuals have defects in activation-induced cytidine deaminase (autosomal recessive inheritance pattern)
• Sx: recurrent pyogenic infections (low levels of opsonizing IgG)
o Those with CD40L mutations are also susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because of the defect in cell mediated immunity
o Also at risk for IgM induced cytopenias (AIHA, autoimmune thrombocytopenia, and neutropenia)
o Patients can also get extensive involvement of the GI tract by polyclonal IgM producing plasma cells
Severe Combined Immunodeficiency
• Represents a group of syndromes all having in common profound defects of both humoral and cell mediated immunity
o Without hematopoietic cell transplantation, death occurs within a year
• Affected infants present with thrush (oral candidiasis), extensive diaper rash, and failure to thrive
o Some infants develop a skin rash shortly after birth due to GVH DZ from maternal T cells that have crossed the placenta
o Patients are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. jiroveci, Pseudomonas, CMV, varicella, and many other bacteria
• Many different genetic lesions can give rise to SCID, and in some instances the genetic defect is not known
o Most common (50-60%) = X-linked, due to a mutation in gene encoding common gamma-chain subunit of CK R
• Results in reduced CK signaling, and T cell development is markedly impaired
• T cell numbers are decreased, and although B cell numbers are normal, antibody synthesis is severely impaired due to lack of T helper lymphocytes; NK cells are also deficient
• Remaining types of SCID are inherited as autosomal recessive disorders
o Most common AR SCID = deficiency of the enzyme adenosine deaminase (ADA)
• Leads to accumulation of deoxyadenosine and its derivatives which are toxic to rapidly dividing immature lymphocytes (especially T lymphocytes)
• Tx: hematopoietic cell transplantation
o Some patients with X-linked SCID have also been treated with gene therapy
• Retroviral vector used to insert a normal cytokine receptor gamma chain gene into the patients bone marrow stem cells which are then transplanted back into the patient
• However, some patients have developed acute T-cell leukemias with this type of therapy
• Some patients with ADA deficiency have also been treated with gene therapy
Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)
• X-linked recessive disorder characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection (usually sinopulmonary) → premature death
• Caused by mutations in gene encoding Wiskott-Aldrich syndrome protein (WASP), located on short arm of X chromosome
o Protein belongs to a family of proteins that are believed to link membrane receptors, including antigen receptors, to actin filaments in cytoskeletal elements → defects in cell migration and signal transduction
• Affected patients experience depletion of T lymphocytes, with variable loss of cell-mediated immunity
o Ab production to polysaccharide antigens absent, low levels of serum IgM (at risk for infections w/ encapsulated orgs)
o IgG levels usually normal, and IgA & IgE levels are often elevate
o Dx genetic tests for WASP mutations are available
• In addition to developing recurrent infections, patients are at risk for non-Hodgkin B cell lymphomas
• Tx: only effective treatment is hematopoietic cell transplantation
X-Linked Lymphoproliferative Syndrome
- Disease characterized by inability to eliminate Epstein-Barr virus (EBV), leading to severe and sometimes fatal infectious mononucleosis and B cell lymphomas
- Most cases are due to mutations in the gene encoding a molecule called SLAM-associated protein, which is involved in the activation of NK cells and T and B lymphocytes
Chediak-Higashi Syndrome
• Rare autosomal recessive disorder characterized by recurrent pyogenic infections, partial oculocutaneous albinism, progressive neurologic abnormalities, and mild coagulation defects
• Gene responsible: CHS1/LYST, part of the BEACH family of vesicle trafficking regulatory proteins
o Results in defective fusion of phagosomes & lysosomes → defective phagocyte function & susceptibility to infections
• Dx: peripheral smear for pathognomonic giant cytoplasmic granules in leukocytes & platelets, confirmed w/ genetic testing
• Tx: hematopoietic cell transplantation (HCT)
Genetic deficiencies of the complement system, as they relate to susceptibility for infections:
• Hereditary deficiencies have been described for virtually all components and several pathway regulators
• Deficiencies of early classical pathway components (C2, C1, C4) show little or no increase in susceptibility to infections, but there is an increased incidence of an SLE-like autoimmune disease
• Deficiency of alternative pathway (properdin and factor D) are rare and are associated with recurrent pyogenic infections
• Deficiency of C3 affects both classical and alternative pathways → susceptibility to serious and recurrent pyogenic infections
o C3 deficiency also results in increased incidence of immune complex-mediated glomerulonephritis
• Deficiencies of terminal components (C5, C6, C7, C8, C9) show increased susceptibility for recurrent neisserial (gonococcal and meningococcal) infections
o Due to impaired function of the membrane attack complex involved in the lysis of organisms
o Neisseria bacteria have thin walls and are especially sensitive to the lytic actions of complement)
Asplenia/hyposplenism
loss of splenic macrophages post splenectomy can lead to increased risk of bacterial infection with encapsulated organisms, particularly with Streptococcus pneumonia
• Patients receive vaccinations for S. pneumoniae, H. influenzae, and N. meningitidis
• Types of grafts:
o Autograft = self to self – ex. skin graft
o Isograft = syngeneic, between identical twins
o Allograft = between genetically different individuals of the same species
o Xenograft = between two species, ex. pig (porcine) heart valve to human
molecular antigens and transplantations
• ABO antigens are expressed on endothelial cells and many epithelial cells
o MHC I molecules (HLA-A/B/C): expressed on all nucleated cells & platelets, not expressed on mature RBCs
o MHC II molecules (HLA-DR): expressed on APCs = macrophages, dendritic cells, B-cells
o In general, ABO and HLA compatible grafts have a better chance of avoiding rejection
• Key HLA loci involved in transplant rejection include HLA-A, HLA-B, HLA-C (minor importance), and HLA-DR
• Cellular rejection
T cell-mediated graft rejection o Involves destruction of donated graft cells by recipient CD8+ cytotoxic T lymphocytes and delayed hypersensitivity reactions triggered by activated recipient CD4+ T helper lymphocytes o Major antigenic differences between donor & recipient that result in rejection of transplants are differences in the highly pleomorphic HLA alleles o Recipient’s T cells recognize donor alloantigens by two pathways, the direct and indirect • Direct pathway: donor class I and class II MHC antigens on APCs in the graft (along with costimulators) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively • CD4+ proliferate & produce CKs (IFN-γ)→ tissue damage by a local delayed hypersensitivity reaction • CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells • Indirect pathway: graft antigens are picked up, processed, and displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed hypersensitivity reaction and stimulate B cells to produce Ab
• Humoral rejection
: antibodies produced against alloantigens in the graft are important mediators of rejection
o These Ab may be preformed (present before the transplant) or develop following the transplant
• Important preformed anti-donor antibodies include:
o Antibodies to ABO blood group antigens (naturally occurring)
o Preformed anti-HLA antibodies (pregnancy, previous transfusion, previous transplant)
o If preformed antibodies are present, a hyperacute rejection reaction is possible
o Antibodies to HLA antigens can also develop following transplantation – can cause injury by several mechanisms
• Complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity
• Antibody-mediated acute rejection is usually manifested in the vasculature, resulting in rejection vasculitis
• Rejection can be classified as
o Hyperacute rejection = result of ABO incompatibility or preformed anti-HLA antibodies in the recipient
• Bind to endothelial antigens, activate complement, and result in vessel thrombi & ischemic necrosis (type II antibody-mediated hypersensitivity reaction)
• Begins suddenly, within minutes to hours following transplant
• = WE GOOFED UP, should not happen
o Acute rejection = T cell-mediated hypersensitivity reactions (host CD4+ T-cells release CKs, activating host macs & CD8+) or from antibody-mediated hypersensitivity reactions (host CD4+ T-cells release CKs which promote B-cells to differentiate into plasma cells that produce anti-HLA antibodies that bind to endothelial antigens)
• Acute rejection occurs over days to weeks.
o Chronic rejection = occurs over months and years and is often secondary to vascular injury, as a result of both cell-mediated and antibody-mediated hypersensitivity reactions
• Chronic rejection is the most common cause of renal graft failure
• Chances of graft survival are improved by:
o ABO & HLA matching between donor and recipient, along with absence of preformed anti-HLA antibodies
• ABO & HLA matching not done in all cases; sometimes possible to perform ABO incompatible transplants!
o Use of immunosuppressive agents, both prior to transplant (desensitization) and after transplant
• Development of effective immunosuppression (initially cyclosporine, followed by azathioprine) made transplantation medicine a success
o Long term immunosuppressive therapy has potential complications, including:
• Increased susceptibility for opportunistic infections (CMV, pneumocystis) + increased susceptibility for common community acquired infectious disease
• Increased risk of malignancies – EBV associated post transplant lymphoproliferative disorders (PTLD), squamous cell carcinoma of skin, and Kaposi sarcoma
Hematopoietic Cell Transplantation
• Tx: hematologic malignancies, non-hematologic malignancies, aplastic anemias, thalassemias, & immunodeficiencies
• HCT = administration of hematopoietic progenitor cells from any source to reconstitute bone marrow
o Sources: bone marrow, peripheral blood, umbilical cord blood
• Autologous HCT (auto-HCT) uses hematopoietic progenitor cells derived from the individual with the disorder
• Allogeneic HCT (allo-HCT) uses hematopoietic progenitor cells collected from someone other than individual with the disorder
o In allogeneic HCT, transplanted immunocompetent T-cells from the donor (graft) may recognize the recipient (host) cells as foreign→ graft-versus-host reaction → graft vs. host disease (GVHD)
