T2 Lecture 6: Transplant/Hypersensitivity Flashcards
Difference between allograft, autograft, syngeneic graft, and xenograft?
Allograft - another person, same species
Autograft - same person
Syngeneic - another person, identical genes
Xenograft - different species
What mediates rejection specifically?
Inflammatory reactions
What mediates graft rejection specifically?
Adaptive immune system due to specificity and memory
What does a graft need to be deemed as to be successful?
The body must recognize the graft as “self”
What molecules does a T cell recognize?
MHC/HLA
When does a transfusion reaction occur?
When a person receives blood with different antigens than their own.
What kind of antigens and antibodies do A blood types have?
A antigens on the surface, B antibodies produced.
What kind of antigens and antibodies do O blood types have?
No antigens on the surface, A and B antibodies produced.
If I mix anti-A and anti-B antibodies and have agglutination with both, what blood type did I mix?
AB
If I mix anti-A and anti-B antibodies and have agglutination with just my anti-A, what blood type am I?
A
If I have no agglutination, what blood type do I have?
O
Which Rh group is the only clinically significant one?
RhD
What does a person with Rh+ blood have?
They have the D antigen present on their RBCs.
What happens when an Rh- and an Rh+ person share blood for the first time?
The Rh- person will start making antibodies (IgG) to the D antigen.
What are the two ways I can trigger the production of IgG in terms of Rh blood groups?
Exposure via pregnancy or transfusion.
What are the major antigen targets of transplant rejection?
MHC/HLA
What is rejection of a transplant mainly due to?
T-cells
What is suppressive therapy?
Therapy to inhibit the immune responses that contribute to rejection.
What are the 3 forms of rejection?
Anti-body mediated (Hyperacute and acute)
Cell-mediated (acute)
Chronic rejection (chronic)
What are the common symptoms of rejection?
General discomfort, uneasiness, or ill feeling
FLS
Dependent on organs as well.
What symptom is common in a pancreatic transplant?
High blood sugar
What symptoms are common in a heart transplant?
SOB and reduced ability to exercise
What symptoms are common in a liver transplant?
Yellow skin color and easy bleeding
What symptoms are common in a kidney transplant?
Oliguria
What is the process of a hyperacute rejection?
Occurs when preformed anti-blood antigen or anti-HLA antibodies bind to vascular endothelial cells of a graft.
Complement is activated
Antibodies against HLA antigens are deposited into the tissue endothelium and vasculature.
Neutrophils, macrophages, and platelets are attracted to the site, causing further cellular damage.
Platelet deposition leads to vascular thrombosis.
When do I typically see hyperacute rejections?
ABO Blood Type Incompatibility
What are the two types of acute rejections?
T-cell mediated or antibody mediated
What is the most common type of rejection?
Acute T-cell mediated rejection
How fast does an acute rejection typically occur within?
1 week
Explain the two processes of a T-cell mediated rejection
APCs present donor alloantigens to host T lymphocytes.
If APCs are from the donor, it is direct activation.
If APCs are from the recipient, it is indirect activation
Explain the mechanism of CD8 cells in T cell mediated rejection
CD8 cells recognize MHC 1 molecules
CD8 differentiate into CTLs
CTLs directly kill graft tissue
Explain the mechanism of CD4 cells in T cell mediated rejection
CD4 recognize MHC 2 molecules
CD4 differentiate into Th cells.
Th cells secrete cytokines to influence other immune cells (B, CD8, macrophages, and NK cells)
What are the effects of cytokines that lead to graft injury?
Increased vascular permeability
Accumulation of immune cells to graft site
Activation of macrophages
Explain the process of antibody-mediated/humoral acute rejection
Occurs as a result of B-lymphocyte proliferation, followed by differentiation into plasma cells.
Plasma cells produce donor-specific antibodies (DSAs)
Previous exposure to a relevant HLA antigen causes rejection but high circulation of antibodies does not occur until after transplantation.
Complement-fixing antibodies are generated -> graft vasculature is targeted and rejection ensues.
Explain the process of chronic rejection
It is immune-mediated inflammatory injury that occurs over the span of years.
This results in residual circulating anti-graft T lymphs or antibodies that compromise graft integrity.
Leads to endothelial smooth muscle thickening and arterial occlusion
What are the characteristics of chronic rejection?
Fibrosis
Vascular injury/impaired blood supply
Loss of graft function
Why does fibrosis occur in chronic rejection?
T lymphocytes and macrophages produce cytokines which attract fibroblasts and infiltrate tissues.
When does GVHD typically occur after?
100 days following a transplant of allogeneic stem cells or bone marrow.
What three requirements must be met for GVHD to develop?
Graft must contain immunologically competent cells
Recipient cells must express antigens that are not present on donor cells
Recipient must be immunologically compromised and incapable of mounting an effective immune response
How often does GVHD occur even in matched HLA patients?
40% of the time
Explain the process of GVHD
Newly transplanted donor T cells react to the HLAs on host cells and attack the recipient’s body.
This is due to the donor T cells recognizing the recipient’s body as foreign.
What three organs systems are most commonly affected in GVHD?
GI tract: diarrhea, abdominal cramping, nausea, and anorexia. Sometimes GI bleeds
Skin: rashes, itching, blisters, and ulcerations (sometimes)
The rashes typically start on hands and feet.
Liver: jaundice, liver disease
What is the main target of immunosuppression?
Inhibit T cell activation and effector functions.
What are the three types of immunosuppressants we typically give for organ transplants?
Cytotoxic drugs
Specific immunosuppressive agents
Anti T cell antibodies
What is current immunosuppressive therapy successful in?
Preventing and reducing acute rejection and GVHD.
When does autoimmunity occur?
The body’s immune system cannot differentiate between self and nonself.
Against what does autoimmunity occur?
self antigens
How much of the US population do autoimmune disease typically affect?
5-8%
List at least 2 organ specific and non-organ specific autoimmune diseases.
Organ-specific: MS, Hashimoto’s, Myasthenia gravis, Addison’s disease, pernicious anemia, Type 1 DM
Non-organ specific: Scleroderma, SLE, RA
What are the two processes self-tolerance relies on?
Central tolerance and peripheral tolerance
Compare and contrast central and peripheral tolerance
Central: Eliminating autoreactive lymphocytes during maturation in the central lymphoid organs.
Peripheral: Functional suppression of autoreactive lymphocytes that escaped destruction in the thymus and are circulating in peripheral tissues.
What are heterogeneous disorders?
Genetic and environmental factors contribute to autoimmune diseases.
What does autoimmunity develop from a loss of?
Self-tolerance
What mechanisms can cause cell injury in autoimmune diseases?
Circulating autoantibodies
Immune complexes
Autoreactive T lymphocytes
What are the principal factors that contribute to the development of autoimmune disease?
Inheritance of susceptibility genes
Environmental triggers (such as infections)
What is significant regarding the hereditary component of autoimmune disease?
Single gene mutations rarely cause autoimmune disease.
It is the combination of susceptibility genes and environmental triggers.
What does T-cell activity depend on?
Expression of MHC-HLA complexes on cellular surfaces
What 4 things can lead to a loss of self-tolerance?
T-cell anergy
Release of sequestered antigens
Molecular mimicry
Superantigen formation
Define T-cell anergy
An antigen-specific T cell cannot respond to a stimulus due to reduced function (dysfunctional T cell)
Define the release of sequestered antigens
Hidden self-antigens that are reintroduced to the immune system
Define molecular mimicry
Similarities between foreign and self-antigens trigger an immune response against autoantigens.
Define superantigen formation
Family of substances (staphylococcal and streptococcal exotoxins) that activate T lymphocytes leading to fever, shock, and death.
What are hypersensitivity reactions?
Abnormal OR excessive activated immune responses that damage host tissue.
They are either aberrant (wrong)
or
Excessive (too much)
What are the two generalized causes of hypersensitivity reactions?
1: Dysregulated or uncontrolled responses to foreign antigens (microbes and noninfectious environmental antigens)
2: Response directed against self-antigens resulting in autoimmune disorders.
Are hypersensitivity reactions humoral or innate? What is the defining feature?
Humoral.
They are antigen-specific.
What are the 4 types of hypersensitivity reactions?
Type 1 - IgE mediated
Type II - antibody mediated
Type III - complement-mediated
Type IV - T-cell mediated
What do the clinical and pathological features of each type of hypersensitivity reaction depend on?
The mechanism of the immune response
Location of target antigen.
What is a type I hypersensitivity reaction? What is it commonly known as?
It is an IgE mediated reaction that is more commonly known as the classic allergic reaction.
Type I officially is known as an immediate hypersensitivity reaction.
What causes a type I hypersensitivity reaction?
Antigens that cause immediate hypersensitivity are known as allergens, which trigger type I hypersensitivity reactions.
What does atopic mean?
A person developing symptoms to an allergen.
Does type I hypersensitivity typically run in the family? How can I tell?
Usually yes, based on the abnormally high levels of IgE present and associated atopy.
However, target organ of the atopic disease is variable.
What are some common allergens?
Inhaled:
Plant pollen, dander, mold, feces (of small things)
Injected:
Insect venoms, vaccines, drugs, therapeutic proteins
Ingested:
Food, oral drugs
What are some common type I hypersensitivity reactions?
Allergic rhinitis, sinusitis (Hay Fever)
Food allergies
Bronchial asthma (Atopic)
Anaphylaxis
Atopic Urticaria
Note: All of these are caused by release of mast cell mediators.
What is a type II hypersensitivity reaction?
Antibody-mediated diseases.
Describe the pathologic mechanism of a type II hypersensitivity reaction.
IgG or IgM antibodies are formed against cells or tissue antigens on the HOST.
Examples of Host antigens:
RBCs
Solid tissue (Self-antigens)
Tissue receptors
The tissue specific antigen that these antibodies recognize determine how the disease works.
What is the injury caused by a type II hypersensitivity reaction?
Inflammation, leading to destruction or dysfunction of cells/tissues.
What are common examples of type II hypersensitivity reactions?
Autoimmune hemolytic anemia
Autoimmune thrombocytopenic purpura
Pemphigus vulgaris
Goodpasture’s syndrome (Anti-Glomerular basement membrane disease)
Acute rheumatic fever
Myasthenia Gravis
Graves’ disease (Hypothyroidism)
Pernicious anemia
What is a type III hypersensitivity reaction? What makes it different from type II?
Type III is an immune complex-mediated disease. It involves IgG and IgM like a type II, but it reacts with soluble antigens (AKA free-floating in the bloodstream)
It creates immune complexes that can then be deposited in various locations, creating either systemic or localized reactions.
What are some common clinical manifestations of type III hypersensitivity reactions?
SLE (Systemic lupus erythematosus) ->Nephritis, arthritis, vasculitis
Polyarteritis Nodosa -> Vasculitis
Postreptococcal glomerulonephritis -> Nephritis
Serum sickness -> Systemic vasculitis, nephritis, arthritis
Arthus reaction -> cutaneous vasculitis
What is a type IV hypersensitivity reaction? What is it commonly known as?
Involves responses initiated by Th-1 cells, caused inflammation due to macrophages and tissue damage via cytotoxic T cells.
T cell-mediated hypersensitivity reactions.
What are the target antigens in a type IV hypersensitivity reaction?
Innocuous environmental antigens (contact dermatitis)
Self antigens part of the immune process
Intracellular pathogens that are difficult to clear out
What are some clinical manifestations of type IV hypersensitivity reactions?
MS (Multiple sclerosis)
RA (Rheumatoid arthritis)
Type I DM (Diabetes mellitus)
Crohn’s disease
Contact sensitivity (such as poison ivy)
Chronic infections (like TB)
Viral Hepatitis (B & C)
Superantigen-mediated diseases (Toxic shock syndrome)
How do we treat hypersensitivity reactions?
Anti-inflammatories
Immunosuppression (if the reaction is self-antigen targeting)
For immediate hypersensitvity:
Antigen avoidance
Desensitization (allergy shots)
What is immunodeficiency?
An abnormality in one or more parts of the immune system, resulting in increased susceptibility to disease that is normally eradicated by a properly functioning immune response, including infection by invading microorganisms or development of neoplastic syndromes.
What are the two types of immunodeficiencies?
Primary/congenital
Secondary/Acquired
What defects in the body cause primary/congenital immunodeficiency?
Defects in:
lymphocyte development
lymphocyte activation
Effector mechanisms of adaptive or innate immunity.
What are the 10 warning signs of primary immunodeficiency?
Frequent ear infections.
Frequent sinus infections.
Prolonged ABX therapy
Little ABX effect
Failure to thrive
Recurrent abscesses
Two deep-seated infections
Persistent thrush or fungus infections
Need for IV ABX to clear diseases
Family Hx of primary immunodeficiency
Note:
All of this to say that you get sick easily, you don’t get well easily, and your family probably had the same stuff.
What is the pathophysiology that leads to primary immunodeficiences?
Since primary immunodeficiency is mainly lymphocyte-based, it is genetic abnormalities that cause altered protein production, which we need to make sure our immune system functions fully.
Ranges in severity greatly.
What is SCID? What are the functional deficiencies of SCID, AKA lab findings?
Severe combined immunodeficiency. AKA bubble boy disease.
Characterized by:
Reduced # of B cells
Reduced # of T cells
Reduced serum immunoglobulin (IgG)
What are some primary features of SCID?
Recurrent infections by 6 months of age, having severe viral/bacterial infections, opportunistic infections, failure to thrive.
Most babies die within a year.
What are the characteristic infections of SCID?
Mycobacterium, Salmonella, Pneumocystis jiroveci, Toxoplasma, Cryptosporidium, Leishmania, Herpesviridae, Varicella Zoster, Cryptococcus, neoformans, Histoplasma capsulatum.
What is a B-cell deficiency? What causes B-cell deficiency and what does the lab finding look like?
It is characterized by a primary genetic defect in antibody genes or in the genes that develop Th cells.
Reduced # of B cells or skewed B cell production (no IgG, no IgA, hyper IgM)
What are some primary features of B-cell deficiency?
Pyogenic bacterial infections
Enteric bacterial/viral infections
In babies: persistent otitis media, pneumonia
In adults: pneumonia, multiple sinus infections
What are the characteristic infections of B-cell deficiency?
Streptococcus pneumoniae
Haemophilus influenza
Giardia intestinalis
Cryptosporidium parvum
What are the two common pure B cell immunodeficiencies? Most common?
X-linked agammaglobulinemia
Selective IgA deficiency (Most common)
What is X-linked agammaglobulinemia also known as? Characteristics?
Bruton type agammagloblulinemia because there is a mutation in the gene for bruton tyrosine kinase, which is needed for B cells to mature.
Result:
Inability to produce B cells or immunoglobulins.
What is selective IgA deficiency? Characteristics/causes?
A condition where you have little to no IgA.
Causes: genetic, sporadic, lack of breastfeeding at birth, medications/viral infections.
It can result in recurrent infections and is associated with autoimmune diseases like RA, Lupus, and celiac.
What is the genetic basis of T cell deficiency? What would I see on lab findings?
Genetic: Defects in genes needed for T cell development or activation, incomplete development of the thymus.
Lab findings: Reduced number of T cells. You sometimes can see reduced serum immunoglobulin as well.
What are the primary features of T cell deficiency?
Severe common viral infections, (RSV, rota, entero viruses), intracellular microbial infections (mycobacteria), virus-associated malignancies (EBV, lymphomas)
What are the characteristic infections of T cell deficiency?
Mycobacterium, salmonella, Rhodococcus, pneumocystis jiroveci, toxoplasma, cryptosporidium, leishmania, herpesviridae, varicella zoster, cryptococcus neoformans, histoplasma capsulatum.
What is the common T cell deficiency we learned about?
Di George syndrome (22q11.2 deletion syndrome)
What is the cause of Di George syndrome and what does it result in?
Familial or sporadic mutations cause an absence in a section of chromosome 22. This part causes poor development of multiple body systems, especially the thymus.
Poor thymus development = low T cell counts = increased susceptibility to infections.
What are some lab findings in someone with an innate immunity deficiency?
Variable, but could be:
Defects in reactive oxygen intermediate production.
Inability to interact with an activated endothelium
Neutropenia with CBC
What are some primary features of an innate immunity deficiency?
Severe infection, or sepsis, absence of pus
What are some characteristic infections of someone with an innate immunity deficiency?
Pneumococcus, Hib, Meningococcus, plasmodium, babesia
What are some common lab findings in someone with a complement deficiency?
Decreased levels of specific complement components or we see disorders that would normally inhibit complement activation on human cells.
What is the primary feature of someone with a complement deficiency?
Increased infections, but most commonly associated with SLE and other autoimmune diseases.
What are some characteristic infections of someone with a complement deficiency?
Neisseria, streptococcus pneumoniae
How do we treat primary immunodeficiencies?
ABX therapy
Periodic injections of IVIG or SCIG
Bone marrow transplant
What are the causes of secondary immunodeficiency?
Immunosuppressive agents
Malnutrition
Aging
Medications (chemo, antirheumatics, immunosuppressants, glucocorticoids)
Cancer (usually bone marrow)
Chronic infections
AIDS
What is AIDS exactly? Cause?
Acquired Immunodeficiency syndrome, caused by HIV.
Which HIV usually causes AIDS in the US?
HIV-1
What cells are affected in AIDS?
CD4 helper cells
Macrophages
Dendritic cells
Describe the pathogenesis of an HIV infection.
- HIV binds to a CD4 cell
- HIV then enters the CD4 cell.
- The HIV uses its reverse transcriptase to convert its RNA to DNA.
- The new viral DNA integrates with the host DNA.
- HIV DNA makes mRNA
- rRNA makes polyproteins from that viral mRNA.
- Cleavage occurs, creating lots of HIV proteins.
- Virus leaves the cell to find more cells.
What are the clinical features of an acute/early infection by HIV?
Generalized fever, headache, sore throat, lymphadenopathy, ashes (or asymptomatic)
Takes 3-6 weeks post infection for symptoms to start appearing.
What are the pathophysiological changes in an acute/early infection by HIV?
Spike of the virus in the blood.
Modest reduction of CD4 cells.
What are the clinical features of the clinical latency period in an HIV infection?
Patients are asymptomatic or get minor infections throughout the years.
It can last for years!!
What are the pathophysiological changes of the clinical latency period for HIV?
Declining CD4 T cell counts
Macrophages and follicular dendritic cells starting becoming reservoirs for HIV.
What are the clinical features of the actual AIDS phase in an HIV infection?
Opportunistic infections
Wasting
Dementia
What are the pathophysiological changes in the actual AIDS phase of an HIV infection?
CD4 cell count < 200.
This is the clinical definition of AIDS.
The lower it goes, the worse the prognosis.
What are some opportunistic infections associated with AIDS?
Parasites:
Toxoplasmas
Cryptosporidiums
Leishmanias
Microsporidiums
Bacteria:
Mycobacterium TB
Mycobacterium avium intracellulare
Salmonellas
Fungi:
Pneumocystis carinii
Cryptococcus neoformans
Candidas
Histoplasma capsulatum
Coccidiodes immitis
Viruses:
Herpes simplex
CMV
Varicella-zoster
What are some malignancies associated with AIDS?
Kaposi’s sarcoma (HHV-8)
Non-hodgkin’s lymphoma, such as EBV-positive Burkitt’s lymphoma.
Primary lymphoma of the brain.
How do we diagnose AIDS?
H&P to check risk factors and S/S.
Lab findings, such as HIV antibody counts, HIV viral load counts, and CD4 Th cell counts.
What drug class is used to treat HIV/AIDS?
Highly active antiretrovirals (HAARTs)
They can delay the progression by suppressing viral entry and replication.
We commonly used combinations to prevent resistance.
What are some common type I hypersensitivity reactions?
Allergic rhinitis, sinusitis (Hay Fever)
Food allergies
Bronchial asthma (Atopic)
Anaphylaxis
Atopic Urticaria
Note: All of these are caused by release of mast cell mediators.
