Module 9 Autoimmunity and Transplantation Flashcards
Histocompatibility
Donor and recipient to have similar tissue types is called histocompatible
Do erythrocytes express HLA?
No, erythrocytes in a blood transfusion do not expressed any HLA class I or II. Conversely, the leukocytes that do Xpress HLA antigens are removed from blood before it is used for transfusion.
Incompatibility of blood group antigens causes Type II hypersensitivity reactions
Antigens A and B, but not O, are structurally similar to carbohydrates on the surface of commensalism bacteria. People lacking the A or B antigens, or both make antibodies against the corresponding carbohydrates of commensal bacteria. Consequently, the serum of people with blood group O invariably contains IgG specific for the A and B antigens. If a group O patient were to be transfused with group A or B blood, the recipients’ anti-A or anti-B antibodies bind to the transfused erythrocytes, causing complement fixation and lysis of all the transfused erythrocytes.
Alloantigens and alloantibodies
Antigens like ABO that differ between the genetically unrelated members of a species are called alloantigens and antibodies made against them are called alloantibodies
RhD- women
Their future pregnancies are potentially susceptible to hemolytic disease of the newborn
What reaction does RhD and ABO cause?
Type II hypersensitivity reaction
Similar to reactions to penicillin, the foreign antigens on the erythrocytes is a result of chemical modification induced by the drug. Whereas the foreign antigen on transfused erythrocyte is an additional sugar attached to the surface glycolipids and glycoproteins. An ABO-incompatible blood transfusion causes extensive erythrocyte lysis, and leads to fever, chills, shock or renal failure, or even death.
Which type of hypersensitivity is hyperacute rejection?
Hyperacute rejection of transplanted organ is a type II hypersensitivity reaction caused by preexisting antibodies of the recipient against donor ABO or HLA class I antigens
ABO and HLA class I are constitutively expressed on vascular endothelium. If the recipient ABO and HLA are not compatible to the donor’s, antibodies in the recipient’s circulation quickly bind to and coat all the blood vessels of the graft. By fixing complement throughout the graft’s vasculature, IgG antibodies cause rapid rejection of the graft. This outcome is described as Hyperacute Rejection, which can occur even before a transplanted patient has left the operating room.
Where do anti-HLA antibodies arise from?
Anti-HLA antibodies, arise from pregnancy, blood transfusion and transplantation
- During birth, mothers can make antibodies against any paternal HLA allotype expressed by the child and not carried by the mother —> more anti-HLA antibodies develop and level of anti-HLA antibodies increase with each successive pregnancies which can complicate any future search for a compatible organ transplant should the mother need one. For example, the father of the child cannot donate a kidney to the mother because her anti-HLA antibodies target his HLA antigens and would cause immediate hyperacute rejection
- During blood transfusion: similar process: the more times a patient accepted blood transfusion, the more antibodies are developed against numerous HLA allotypes
- Transplantation: similar process.
Panel Reactive Antibody (PRA)
The patient’s serum is tested for reactivity with leukocytes obtained from a panel of individuals representing all the common HLA class I and class II antigens. The number of positive reactions is expressed as a percentage panel reactive antibodies. The higher a patient’s PRA, the more difficult it is to find a patient a donor.
Which type of hypersensitivity reactions are acute transplant rejection and GvHD?
Acute transplant rejection and GvHD are type IV hypersensitivity reactions.
Self antigens, such as HLA I and II, that vary within a species are called alloantigens, and the immune responses they provoke are called alloreactions. A su field of immunology , immunogenicity’s, is devoted to the genetics of alloantigens and their impact on immunity.
Mixed lymphocyte reaction
An analogous cellular test that has been used prospectively to assess how a patient’s T cells might respond to a transplanted organ from a living donor
It is an in vitro model of acute rejection
Rarely used to now given the time taken to perform the test, having been replaced by matching of DNA sequences for the polymorphic exons of HRA class I and class II genes
Why is HLA matching important?
During their coevoluation over some 500 millions years, MHC proteins and TCR have acquired an inherent affinity for each other. Thus the TCR of double positive thymocytes developing in the thymus form a primary repertoire in which all the receptors have some specificity for MHC molecules
Hence negative selection for self MHC is important, as it leads to the retainment of TCR with only moderate affinity for self MHC
In a mixed lymphocyte, a reaction between cells from HLA-disparate individuals, around 5% of the T cells have the potential to respond to a particular foreign HLA class I or class II alloantigens. This response is far greater than that to most of microbial or viral antigens, and is comparable to that induced by a bacterial superantigen.
What is direct pathway of allorecognition?
An alloreactive response in which the recipient’s T cells are stimulated by direct interaction of their TCR with complexes of allogeneic HLA molecules and donor peptides on donor dendritic cells is call the direct pathway of allorecognition.
Chronic rejection of transplanted organs
Equivalent to a type III hypersensitivity reaction
Grafts undergoing chronic rejection are infiltrated with CD40 expressing B cells and helper T cells expressing CD40L. The contribution of help T cells can be also considered a type IV hypersensitivity reaction. The B cell-specific antibody, rituximab is used to treat chronic rejection.
Differences between direct and indireact pathway of allorecognition
Dendritic cells from an organ graft stimulate both the direct and indirect pathways of allorecognition.
However, activation of alloreactive T cells by the direct pathway of alloantigen recognition wanes overtime. This decrease correlates with the elimination of the DC of donor region, and their replacement in the transplanted organ by immature DC of recipient origin.
The indirect pathway of allorecognition is responsible for stimulating the production of the anti-HLA antibodies that cause chromic graft rejection
Most important HLA types that need to match?
HLA-A, B, C and DR allotypes are the most important ones to match
Anti-CD52 drugs
CD52 is expressed on most lymphocytes, monocytes, and macrophages.
Anti-CD52 antibodies induce a profound, unusually efficient in fixing complement, which is attributed to the distinctive structure of CD52.
Corticosteroids / Prednisone
- Synthetic derivative of hydrocortisone (also called cortisol), the principal steroid made by the adrenal cortex.
- It is a prodrug, meaning it is taken by patients in an inactive form, and a converted In Vivo to its active form, prednisolone
- Corticosteroids have a wide range of physiological effect and affect all leukocytes as well as other cells. The transcription of about 1% of genes is influenced by corticosteroids.
- They are most effective given prior to the transplant
How does Cyclosporin and Tacrolimus work to inhibit T cell activities?
They inhibit the serine / threonine phosphatase calcineurin and in turn inhibit the transcription factor AP-1 activity
What effects do Cyclosporin and Tacrolimus have?
OKT3
CD3 specific mouse monoclonal antibody
Works by causing the TCR complex to be internalized and thus unable to recognize antigen
Belatacept
It targets the co-stimulation of T cells and is a synthetic fusion protein that combines the extra cellular B7 binding domains of CTLA4 with the Fc fragment of IgG1
CTLA4 is an inhibitory receptor on T cell and binds B7 with 20 times the strength of CD28, so that when CTLA4 is expressed in outcompetes CD28 in binding B7
How does Basiliximab and Daclizumab work?
Three signals are needed for T cell activation:
- Activating signals from TCR after engaging with MHC and antigen complex
- CD28: B7 con-stimulatory signals
- Signals from the IL-2 receptor
Naive T cells only express the low-affinity IL-2 receptor, consisting of the beta and gamma chains. Once recognizing an antigen, signals from the TCR initiate synthesis of the alpha chain / CD25, which then associates with the beta and gamma chains to form high-affinity IL2 receptor
Basiliximab and Daclizumab are anti-CD25 antibodies; they work by bind tightly to the high-affinity IL-2 receptor of T cells being activated and prevents the interaction between IL2 and IL2R
Azathioprine
A cytotoxic drug
Affects all dividing cells by preventing the biosynthesis of purine nucleotides
They have severe side effects: they affect bone marrow, intestinal epithelium, and hair follicles
Cyclophosphamide
Was developed as a chemical weapon and much used during WWI. It is a prodrug that metabolized to phosphramide mustard, which alkylates and cross-links DNA to disrupts DNA replication and cell division
Methotrexate
One of the first cytotoxic drugs shown to be effective against cancer. It prevents DNA replication by inhibiting dihydrofolate reductase, an enzyme essential for thymidine biosynthesis
Corneal allograft
Does not require HLA matching or any immunosuppressive drugs and successful 90% of the time
Why is it important to have HLA matching for hematopoietic stem cell transplantation?
- To prevent GvHD
- To reconstitute T-cell function
Minor histocompatibility antigen
How does NK cells mediate graft versus leukemia effects
As a rule, NK cell alloreactions occur when the recipient’s HLA class I provides ligands for fewer inhibitory KIRs than the donor’s type
HLA and autoimmunity
HLA is the dominant genetic factor affecting susceptibility to autoimmune disease
HLA genes account for 50% of the genetic predisposition to autoimmune conditions
The haplotype that encodes the combination of HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2 allotypes is characteristic of populations of European origin, in which it reaches a frequency of up to 11% and associated with SLE, MG etc
Autoimmune disease is more prevalent in women than in men
Women make stronger adaptive immune responses to infection than men.
Estrogen 17-beta estradiol and the peptide hormone prolactin enhance adaptive immunity
Testosterone and progesterone are immunosuppressive and can reduce the production of inflammatory cytokines, antibodies, Th1 cells and NK cells while favoring the production of anti-inflammatory Th2 cytokines
What diseases are mediated by specific antibodies binding to cell-surface receptors
Autoantibodies can act as receptor agonists or antagonists
Graves’ disease
Graves’ disease is caused by a agonist autoantibodies specific for the TSH receptor;
By mimicking the natural Ligand, the antibodies bound to the TSH receptor cause chronic overproduction of thyroid hormones that is independent of regulation by TSH and insensitive to the metabolic needs of the body
Graves’ opthalmopathy: outwardly bulging eyes and a characteristic stare. Caused by autoantibodies that bind to eye muscle
Graves’ disease is driven by a CD4 Th2 response, associated with HLA-DR3. This points to the autoimmune response being initiated by a Th2 cell that recognizes a peptide derived from the TSH receptor presented by HLA-DR3. Such a Th2 could then cooperate with B cells specific for epitopes of the TSH receptor
Myasthenia gravis
Antagonistic autoantibodies bind to the acetylcholine receptors on muscle cells, inducing their endocarditis and in trace lunar degradation by lysosomes —> loss of the receptors from the cell surface makes the muscle less sensitive to neuronal stimulation —> progressive muscle weakness
Myasthenia gravis is associated with HLA-DR3 and CD4 Tfh cells.
What is tertiary lymphoid tissue?
Chronic thyroiditis is an autoimmune disease caused by a CD4 Th17 response that perturbs the thyroid tissue.
A characteristic of chronic thyroiditis is that the lymphocytes and other cells infiltrating the thyroid gland become organized into structures having the typical microanatomy of secondary lymphoid organs. These structures, called tertiary lymphoid structures
Autoimmune diseases of endocrine tissue
Pemphigus vulgaris
Skin-blistering diseases caused by IgG directed at desmogleins, the adhesion molecules that bind the keratinocytes to each other.
Epitope spreading: progressive involvement of different episodes is called epitope spreading
Intramolecular epitope spreading: when the immune response targets different episodes in the same molecule, as it does in pemphigus, this is called intramolecular epitope spreading
Systematic lupus erythematosus
Characterizing SLE are antibodies against the nuclei and protein components of nucleoprotein particles.
Each response is initiated by a loss of T cell tolerance and the activation of a clone of auto reactive T cells with specificity for a peptide cleaved from the nucleoprotein complex and presented by HLA-DR. Cells from the initiating close of T cells activate B cells of many different specificities, the only requirement being that the B cell receptors binds and internalized the complex and presents the peptide recognized by the T cell. The is mechanism allows peptide specific T cells to help B cells make high-affinity antibodies against nucleic acids — macromolecules not recognized by T cells.
Once activated, B cells broaden the T cell response. By presenting many peptides derived from the nucleoprotein complex, the B cells activate the many different T-cell clones specific for those peptides. THis activated is achieved by cognate interactions between B cells and T cells.
IVIG as a therapy for autoimmune disease
IVIG is a mind-boggling mixture of antibodies from thousands of blood donors, contains some antibodies that inhibit the autoimmune antibodies by covering up their antigen-binding sites and preventing them from binding specific autoantigens.
- IVIG attenuates the function of circulating autoantibodies by decreasing their half-life and preventing their recruitment of effector functions.
- It inhibits the production of antibodies by B cells and plasma cells and suppresses the activation of naive auto reactive B cells
what is Rheumatic fever
The classic example of an autoimmunity being caused by an immune response to infection
Celiac disease
Hypersensitivity to food that has much in common with autoimmune disease
The disease affects up to 2% of people of European origin and is caused by an immune response to the gluten proteins of wheat flour or to the related proteins of barley and rye, all of which are majorly components of western diets
Disease is caused by the selective destruction of intestinal epithelial cells
