Immunopathology Flashcards
DiGeorge Syndrome
Caused by a large deletion on chromosome 22 which alters development of the thymus, parathyroids, and great vessels of the heart; characterized by absent T cells (B cells are normal)
C - Cardiovascular abnormalities A - Abnormal face T - Thymus abnormalities C - Cleft H - Hypoparathyroidism 22
Severe Combined Immunodeficiency (SCID)
The most severe of the immunodeficiency syndromes, caused by a block of maturation of the hematopoietic stem cell to pre-T and pre-B lineage precursors
Half of cases are X-linked recessive IL-7R deficiency; half are adenosine deaminase (ADA) deficiency causing adenosine to accumulate in lymphocytes, impairing their development into B cells and T cells
Characterized lymphopenia of T and B cell lineages
Treatment: PEGylated ADA (for AR cases); irradiated RBCs and bone marrow transplantation can be successful, but GvH is a major risk
X-linked (Bruton’s) hypogammaglobulinemia
Caused by a block in B cell maturation from Pre-B to mature B cell stages due to defective Btk tyrosine kinase, important in the development of B cells
Characterized by low to absent B cells in the serum (serum IgG < 10% of normal); T cells are normal
Kids can’t be screened at birth because maternal IgG is present; kids are treated with IVIG
Common variable immunodeficiency
B cells are present but difficult to stimulate into making specific antibody; caused by defects in one or multiple pathways necessary for B cell activation
Often treated with IVIG as needed
X-linked hyperIgM Syndrome
Caused by a defect in CD40L on Tfh cells and CD40 on B cells, which facilitate the class-switching interaction
Characterized by high IgM and low IgG
Selective IgA deficiency
The most common immunodeficiency disease (1/500)
Usually asymptomatic although patients may experience GI infections, sinopulmonary infections, or allergies
10-15x more frequent in people with celiac disease
What infections are associated with pure B cell deficiency?
Associated with infection by extracellular (high grade) pathogens:
Staph aureus
Haemophilus influenza
Streptococcus pneumonia
What infections are associated with pure T cell deficiency?
Associated with infections caused by intracellular pathogens including viruses, yeast, and fungi:
Candida albicans
Pneumocystis jirovecii
Autoimmune hemolytic anemia
Type II Immunopathology
Characterized by the production of anti-RBC antibodies, often following viral infection or drug exposure
“Cold” antibodies bind RBCs in the extremities and dissociate at warmer core temperatures; complement is activated and lyses the RBC
“Warm” antibodies bind RBCs in the core and mediate cell destruction in the spleen
Myasthenia Gravis
Type II immunopathology
A disease of progressive muscle weakness caused by the production of auto-antibody against the acetylcholine receptor (AChR) on the neuromuscular end plate; neutrophils release digestive enzymes at the NMJ resulting in synaptic destruction
Caused by the presence of a certain allele of CHRNA1 coding for the AChR which does not interact with AIRE; therefore, the AChR gene is not expressed in the thymus and AchR-reactive Tfh cells are available to help B cells make antibody to the receptor
Hashimoto’s Thyroiditis
Type II immunopathology
Caused by the production of autoantibodies to thyroid antigens; the thyroid is infiltrated by T cells resulting in tissue destruction and hypothyroidism
Long acting Thyroid Stimulator (LATS)
An IgG auto-antibody to the TSH receptor on thyroid cells found in the blood of most patients with hyperthyroidism; LATS binds the TSH receptor mimicking TSH and causing extended release of thyroid hormones
Autoimmune thrombocytopenic purpura (ATP)
Caused by the production of autoantibodies against platelets; platelets become opsonized by complement and their destruction occurs in the spleen
Inappropriate tachycardia
Caused by the production of autoantibodies to the B-adrenergic receptor on the heart; these antibodies mimic the receptor’s endogenous signaling molecules and cause inappropriate cardiovascular stimulation
Rheumatic Heart Disease
Defined as heart disease occuring shortly after streptococcal infection; caused by cross-reaction between anti-strep antibodies and the antigen laminin found on heart valves, followed by neutrophil-mediated tissue destruction
Dressler syndrome
Caused by the creation of autoantibodies against pericardial or myocardial antigens following heart attack
Characterized by persistent cardiac pain, fever, malaise, and pericardial effusion seen post-MI; treated with anti-inflammatory agents
Goodpasture’s Syndrome
Caused by production of autoantibodies to Type IV collagen in the basement membrane of lung and kidneys; presents as glomerulonephritis and pneumonitis
Diagnosis: A biopsy of the patient’s kidney or lung will have IgG on its basement membrane; adding labeled anti-IgG will allow visualization of these autoantibodies in a “sharp” pattern of fluorescence
Innocent bystander phenomenon
Antibody-mediated damage to tissue that happens to be associated with an antigen
Ex: A drug adheres to RBCs and the body makes antibody to the drug, lysing RBCs in the process
Mechanism of antigenic carrier coupling
Many B cells in the body are auto-reactive but never activated against self antigen because they never receive the proper signaling from Tfh cells; if a foreign antigen is coupled to a self protein, the foreign protein may be taken up with the self protein by a B cell, digested, and loaded onto MHC-II on the B cell surface; now, Tfh cells will recognize the foreign antigen presented by the B cell and stimulate it to secrete it’s own, anti-self antibody
Tissue damage via exposure of a sequestered antigen
Occurs when an immune response is initiated in an anatomical location where a previously sequestered antigen was separated from the general system
Ex: Some men who get mumps become sterile because mumps breaks down the blood/testes barrier, allowing immunization to these normally sequestered sperm antigens
AIRE
A TF driving thymic expression of various extra-thymic proteins; developing T cells that are exposed to these preoteins in the thymus are deleted via negative selection so they do not become auto reactive
How does the Mantoux PPD test work?
PPD tuberculosis antigen is injected intradermally; the antigen is taken up by local macrophages and dendritic cells, which present it on MHC-II. If the patient has an increased number of circulating anti-TB Th1 memory cells from a prior exposure they will be stimulated to produce IFNy and attract M1 macrophages. After 48 hours, the test is read as positive if it is red, expanded, and firm, indicating infiltration of macrophages.
How does the Quantiferon Gold TB test work?
Best practice for patients previously immunized with BCG (bovine TB) vaccine
The patient’s blood sample is mixed with human TB antigens that are specifically known NOT to cross react with bovine TB; the antigen is taken up by antigen-presenting cells in the blood causing Th1 cells to react and the sample is assayed for the presence of IFNy from activated Th1 cells
Delayed hypersensitivity - initiation phase
Exposure to the toxic agent occurs allowing the toxin to penetrate intact skin and associate with MHC-II on dendritic cells; DCs travel to the draining lymph nodes where they present the antigen to Th0 precursors which develop into Th1 cells and divide. By the time increased numbers of activated Th1 cells enter circulation and reach the site of exposure the antigen has worn off of the skin and there is no reaction; immunization occurs but is asymptomatic
Delayed hypersensitivity - Elicitation phase
Following immunization, a subsequent exposure to the same antigen will trigger a delayed hypersensitivity reaction; the antigen penetrates skin and associates with MHC-II on antigen-presenting cells; this time, memory T cells from the pre-existing expanded clones become activated in the area of exposure; these cells secrete IFNy which attracts M1 macrophages and the result is local inflammation peaking 24-48 hours after exposure
Hyperacute rejection
Occurs when a graft is given to a donor who already has pre-existing antibodies to the donor’s MHC, as in the case of a previous graft; the graft is rejected even before it becomes perfused
Common in xenografts due to pre-existing antibody to ubiquitous carbohydrate epitopes that are present in the foreign species but not in the human
3 requirements of GvH
- Graft must contain immunocompetent T cells
- Graft T cells must recognize at least one host antigen as foreign
- Host must be immunosuppressed or unable to recognize the graft’s MHC antigens
GvH is seen mostly in situations where bone marrow is transplanted into immunocompromised patients
How is Type I Diabetes related to autoimmunity?
Antibody to insulin-producing islet Beta cells can be detected in the serum of over 90% of patients with DM Type I
Additionally, there is a strong association between HLA-DQ2 and HLA-DQ8 and DM Type I - these DQ genes have unusual amino acid placements in the antigen-binding groove that allows ready presentation of islet cell-associated peptides
Which HLA allele is associated with DTH reaction to Abacavir?
HLA-B*5701
Normal & pathologic cytokine environment of Peyer’s patches
Submucosal Peyer’s patches are high in TGF-B, which favors differentiation of Th0 cells into Treg cells (anti-inflammatory cells)
When pathogenic bacteria invade and damage cells gut epithelia TLRs recognize PAMPs and DAMPs; IL-6 is produced which, in combination TGF-B, up regulates the differentiation of Th into Th1, Th2, and Th17 (pro-inflammatory cells)
Crohn’s Disease & Ulcerative Colitis - Phenotypic Differences
Crohn’s affects the large and small intestine, especially the terminal ileum in a “patchy” pattern of transmural inflammation characterized by microabscesses in the intestinal wall which may progress to granulomas, and fistulas between the lumen and peritoneum
Ulcerative colitis is usually characterized by mucosal (superficial) inflammation in the large intestine; may erode the intestinal surface, causing bleeding
Inflammatory Bowel Disease - Whats going on?
“Chronic frustrated immune response” - IBD patients have activated Th1, Th17, and Th2 against normal commensal gut organisms
One theory suggests that some IBD patients may have increased gut permeability so that secreted defensins, made by gut lining cells, can penetrate back into tissues where they act as DAMPs stimulating macrophages to produce cytokines, including inflammatory IL-6
Role of T cells in Celiac Disease
90% of Celiac patients are HLA-DQ2 or HLA-DQ8
These MHC-II alleles recognize gluten and present it to Th0 cells, inducing the activation of Th1, Th2, and Th17 against gluten in the gut
Role of B cells in Celiac Disease
The enzyme transglutaminase binds gluten as the first step of digestion; if it couples to but can’t release digestion-resistant gluten peptides then the immune system “sees” it as a self-peptide coupled to a foreign antigen; it may be taken up by a normally inactivated anti-transglutaminase B cell, which can then present the gluten peptide on its MHC-II (HLA-DQ2 or HLA-DQ8) thereby stimulating anti-gluten helper T cells to activate the B cell against self-transglutaminase
(This is the “illicit help” mechanism)
Chronic Beryllium Disease
A pulmonary inflammatory and fibrotic disease caused by exposure to inhaled beryllium dust
Inhaled Be can become covalently linked to various peptides, creating novel epitopes which may be recognized by antigen-presenting cells, stimulating a Th1 response followed by a scarring Th2 response since the Be cannot be effectively removed
It is strongly linked to HLA-DP alleles that have a negatively charged pocket which binds a Be+ coupled peptide
Old Friends Hypothesis
States that certain normal flora have been in humans so long that we rely on their presence to instruct our immune systems not to over-react to the presence of harmless bacteria; i.e. to adequately express Treg cells
In areas where exposure to these commensal agents is reduced, people may be more prone to over-produce Th1, Th2, and Th17 responses to organisms that are non-threatening
Why is the Whipworm study important?
A group of Crohn’s Disease patients were fed a drink containing pig whipworm ova; the mechanism of the patients’ improvement has been shown to be an increase in Treg in the gut, which suppresses Th1, Th17, and Th2 responses
Mechanism of basement membrane damage in Type III Immunopathology
Antibody / antigen complexes ~1,000,000 Daltons are big enough to activate complement but are too small to be cleared by the reticuloendothelial system
Complexes become lodged in the basement membranes; there they activate complement by binding C1 through the classical cascade; C3a and C5a attract neutrophils which arrive and release inflammatory cytokines, causing damage to the basement membrane
Mechanism of one shot serum sickness
Development of fever, rash, itch, arthralgia, increased CRP, increased ESR 10-14 days after exposure to an exogenous antigen (i.e. animal antiserum)
Initially, the system is in antigen excess and Ab-Ag complexes are too small to activate complement; as the immune system makes more antibodies, the system reaches equivalence and Ab-Ag complexes become large enough to lodge in basement membranes
Symptoms persist for about 1 week until the body makes enough antibody to rid itself of antigen through Ag-Ab complexes that can be cleared by the RES
Arthus reaction
Occurs following a secondary exposure to foreign (antigenic) serum; i.e. flu shot, vaccine booster
Pre-existing antibodies to the immunogen exist; when the antigen is deposited by injection, local Ab-Ag complexes form quickly (4-6 hours), activating complement and causing self-limiting tissue soreness
Polyarteritis Nodosa
Antibody complexed with viral Hepatitis B and C proteins commonly lodge in the basement membrane of medium arteries, causing this vascular inflammatory condition
Why can Immunopathology III cause hives?
Immune complexes activate complement; C3a and C5a are anaphylatoxic, stimulating mast cells to release histamine
Streptococcal Glomerulonephritis
Complexes form between Streptococcus pyogenes and its antibody; if complexes happen to be the right intermediate size they can lodge in the basement membrane of the glomerulus causing the onset of nausea, vomiting, fever, reduced urine output, hematuria, and rash over the course of 10-14 days
Hypersensitivity pneumonitis (Farmer’s Lung)
Caused by chronic exposure to thermophilic Actinomycetes bacteria, found in moldy hay
The farmer develops anti-Actinomycetes IgG in the serum; one day, the farmer may inhale enough antigen to form Ag-Ab complexes in the lungs that lodge in the alveolar capillaries where they activate complement, causing neutrophil-mediated inflammation and tissue damage
Rheumatoid Factor
IgM antibody to self-IgG
Diagnostic for Rheumatoid Arthritis
Systemic Lupus Erythrematosus (SLE)
Autoimmune condition caused by the production of IgG antibody to dsDNA
UV radiation damages cells, causing them to release their dsDNA; most of these cellular contents are taken up by macrophages but some free dsDNA exists in the blood stream to form immune complexes with anti-DNA IgG
Immune complexes commonly lodge in the basement membranes of the kidneys, causing glumerulonephritis; children often present with butterfly facial rash
IgA Nephropathy
1 cause of renal transplant worldwide
Caused by deposition of anti-IgA IgG / IgA1 immune complexes in the renal glomerulus
IgA1 has an unusual hinge region creating a novel carbohydrate epitope that ends in N-acetyl-galactosamine; cross-reactive antibodies to this epitope are common in human plasma
How do T and B cells respond to parasites?
Parasitic antigens are presented by APCs which preferentially activate Th2 cells as well as Tfh cells
Th2 recognizes parasite antigens presented on APC, releasing IL-4; IL-4 activates M2 macrophages which “wall off” the pathogen and is chemotactic for eosinophils
Tfh cells stimulate B cells to produce anti-parasite IgG and IgE
Parasite IgE becomes loaded onto the surface of tissue mast cells, where it can cross-link parasite antigens, triggering a large degranulation of histamine
How do eosinophils respond to parasites?
Eosinophils are attracted by release of “ECF-A”; they recognize and bind the Fc end of IgG coating the parasite, triggering release of their granulocytic contents including Major Basic Protein which is highly toxic to helminths
Late phase reaction
Activated mast cells induce Phospholipase A to cleave arachidonic acid from membrane phospholipids; arachidonic acid can be converted by the COX pathway to Prostaglandins and by the lipoxygenase pathway to Leukotrienes; these compounds initiative inflammation, constrict bronchioles, and are together called “eosinophil chemotactic factor of anaphylaxis” (ECF-A) because they are chemotactic for eosinophils
The late phase occurs over 4-10 hours and is not affected by anti-histamines; better treated with anti-inflammatory agents
What is a hive?
A central swelling (wheel) surrounded by an area of redness (flare); wheels are soft and edematous (not inflammatory) and flares are caused by dilation
Atopic
Predisposed to allergies
Oral allergy syndrome
Antigens can pass through the mucous membranes of the mouth to gain access to and activate local mast cells; occurs as a result of cross-reaction of IgE made against pollen with the antigen
Symptoms include tingling lips and tongue, itching, and swelling of the lips; systemic effects are not observed because the antigens are destroyed in the stomach
Hyper IgE Syndrome
AKA “Job” Syndrome
Caused by inability to make IFNy effectively; this leads to poor Th1 response and a predominance of Th2 cells
Epidemiology of allergic diseases
15% of people will experience allergic symptoms throughout their lives; 35% for a newborn with one allergic parent and 65% for a newborn with two allergic parents
Allergic seasonal rhinitis is the most common
Food allergy
Eczema
Asthma
Immediate reaction of Type I Hypersensitivity
IgE binds mast cells with extremely high affinity; thus, plasma levels are very low because all of the IgE is loaded onto mast cells
IgE-loaded mast cells are triggered to degranulate when two adjacent IgE molecules are cross-linked by allergen; this requires the presence of clonal IgE which can respond to different epitopes on the same antigen
Degranulation releases pre-formed histamine, heparin, enzymes, and TNF; “hive” formation occurs rapidly and the reaction is transient as the factors are degraded
The immediate reaction can be blocked by anti-histamines
Immunotherapy
“Allergy shots” - dilute solutions of allergen extracts, given subcutaneously with increases in the concentrated as tolerated
75% of people with seasonal rhinitis say they receive some relief after treatment
The mechanism may have to do with production of IgG antibody response against the antigen, which “traps” and clears the allergen before it can reach IgE-loaded mast cells
