Inflammation & Autoimmune Disorders Flashcards
Acute inflammation is characterized by presence of ____ and _____ in tissue
It arises in response to ______ or _____ _____ with the goal to eliminate pathogen or clear debris. Also important to note is that it is an immediate response with LIMITED specificity — which is a hallmark of innate immunity.
Edema; neutrophils
Infection; tissue necrosis
Innate immunity is mediated by several factors. ______ are present on cell of innate immune system including macrophages and dendritic cells, and recognize and are activated by PAMPs
TLRs
Pathogen-associated molecular patterns (PAMPs) are commonly shared by microbes. _____ is an example of a PAMP on the outer membrane of gram-negative bacteria that is recognized by CD14 on macrophages
LPS
Activation of a TLR upon recognition of a PAMP results in upregulation of ______, which activates immune response genes and leads to production of multiple immune mediators.
NF-kB
T/F: TLRs are only present on cells of innate immunity
False — they are also present on cells of adaptive immunity in which case they mediate chronic inflammation
______ _____ is an immune mediator released from the phospholipid cell membrane by phospholipase A2.
It is then acted on by _______ or ________
Arachidonic acid
Cyclooxygenase; 5-lipooxygenase
Arachidonic acid is an immune mediator released from the phospholipid cell membrane by phospholipase A2. It is then acted on by cyclooxygenase or 5-lipooxygenase.
Cyclooxygenase produces ________.
Of these, ___________ (3) mediate vasodilation and inceased vascular permeability. ______ also mediates fever and pain
Prostaglandins
PGI2, PGD2, PGE2; PGE2
[NOTE vasodilation occurs at the level of the ARTERIOLE and the increased vascular permeability occurs at the level of the POST-CAPILLARY VENULE]
Remember EEEEEEE2 controls feeeeeeeever
Arachidonic acid is an immune mediator released from the phospholipid cell membrane by phospholipase A2. It is then acted on by cyclooxygenase or 5-lipooxygenase.
5-lipoxygenase produces _______.
Of these, _____ attracts and activates neutrophils and __________ (3) mediate vasoconstriction, bronchospasm, and increased vascular permeability
Leukotrienes
LTB4; LTC4, LTD4, LTE4
[increased vascular permeability is d/t contraction of pericytes]
Mast cells are an inflammatory mediator widely distributed throughout connective tissue of the body. What are the 3 ways in which mast cells are activated?
Tissue trauma
Complement proteins C3a and C5a
Cross-linking of cell-surface IgE by antigen
Immediate response of mast cell activation involves release of preformed ____ granules which mediate vasodilation of arterioles and increased vascular permeability. The delayed response involves production of _____ _____ metabolites, particularly ______
Histamine; arachidonic acid; leukotrienes
Complement are proinflammatory serum proteins that enhance inflammation. They circulate as inactive precursors. What are the 3 ways in which complement activation can occur?
Classical pathway — C1 binds to IgG or IgM that is bound to antigen
Alternative pathway — Microbial products directly activate complement
Mannose-binding lectin pathway — MBL binds mannose on microorganisms and activates complement
The result of complement activation by any of the 3 pathways is generation of C3 convertase, C5 convertase, and formation of MAC. Key products generated by complement include C3a and C5a, C3b, and the MAC.
What is the specific function shared by C3a and C5a?
C3a and C5a trigger mast cell degranulation
The result of complement activation by any of the 3 pathways is generation of C3 convertase, C5 convertase, and formation of MAC. Key products generated by complement include C3a and C5a, C3b, and the MAC.
C3a and C5a trigger mast cell degranulation. What is the other function of C5a?
Chemotactic for neutrophils
The result of complement activation by any of the 3 pathways is generation of C3 convertase, C5 convertase, and formation of MAC. Key products generated by complement include C3a and C5a, C3b, and the MAC.
What is the specific function of C3b?
Opsonin for phagocytosis
[opsonins basically tag things for destruction]
The result of complement activation by any of the 3 pathways is generation of C3 convertase, C5 convertase, and formation of MAC. Key products generated by complement include C3a and C5a, C3b, and the MAC.
What is the specific function of the MAC?
Lyses microbes by creating holes in the cell membrane
[MAC is formed by C5b joined with C6-9]
Inactive proinflammatory protein produced in the liver; activated upon exposure to subendothelial or tissue collagen
Hageman factor
[plays an important role in DIC]
Hageman factor activates coagulation and fibrinolytic systems (role in DIC), complement, and kinin system. What is the role of the kinin system?
Cleaves HMWK to bradykinin, which mediates vasodilation, increased vascular permeability, and pain
The cardinal signs of inflammation include redness (rubor), warmth (calor), swelling (tumor), pain (dolor), and fever. What is the physiology behind redness and warmth (including key mediators)?
Due to vasodilation which results in increased blood flow via relaxation of arteriolar smooth muscle
Key mediators are histamine, prostaglandins, and bradykinin
The cardinal signs of inflammation include redness (rubor), warmth (calor), swelling (tumor), pain (dolor), and fever. What is the physiology behind swelling (including key mediators)?
Due to leakage of fluid from postcapillary venules into interstitial space
Key mediators are histamine and tissue damage
The cardinal signs of inflammation include redness (rubor), warmth (calor), swelling (tumor), pain (dolor), and fever. What is the physiology behind pain (including key mediators)?
Bradykinin and PGE2 sensitize sensory nerve endings
The cardinal signs of inflammation include redness (rubor), warmth (calor), swelling (tumor), pain (dolor), and fever. What is the physiology behind fever (including key mediators)?
Pyrogens cause macrophages to release IL-1 and TNF
Increase COX activity in perivascular cells of hypothalamus
Increased PGE2 raises temperature set point
Step one of neutrophil arrival and activation is ______ which is characterized by vasodilation which slows blood flow in postcapillary venules and cells move to periphery of flow
Margination
Step one of neutrophil arrival and activation is margination. Step two is rolling, which requires selectin upregulation on endothelial cells. What are the 2 important selectins?
P-selectin is released from Weibel-Palade bodies (in endothelial cells); mediated by histamine
E-selectin is induced by TNF and IL-1
[Remember Weibel-Palade bodies contain P-selectin and vWF]
Step one of neutrophil arrival and activation is margination. Step two is rolling, which requires selectin upregulation on endothelial cells. Selectins bind __________ on leukocytes, an interaction which then results in rolling of leukocytes along the vessel wall
Sialyl Lewis X
Step one of neutrophil arrival and activation is margination. Step two is rolling, which requires selectin upregulation on endothelial cells. Step three is adhesion, which is an interaction resulting in firm adhesion to the vessel wall. This requires cell adhesion molecule upregulation on the endothelium by ____ and ____. In addition, integrins are upregulated on leukocytes by ____ and ____
TNF; IL-1
C5a; LTB4
Leukocyte adhesion deficiency is an _____ ____ inherited defect of _______
Autosomal recessive; integrins (CD18 subunit)
3 key clinical features of Leukocyte Adhesion Deficiency
Delayed separation of umbilical cord
Increased circulating neutrophils
Recurrent bacterial infections that LACK pus formation
Step one of neutrophil arrival and activation is margination. Step two is rolling, which requires selectin upregulation on endothelial cells. Step three is adhesion via integrins and cell adhesion molecules. Step four is transmigration and chemotaxis. During step four, leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants. What are the 4 key chemoattractants for neutrophils?
LTB4
C5a
IL-8
Bacterial products
Step one of neutrophil arrival and activation is margination. Step two is rolling, which requires selectin upregulation on endothelial cells. Step three is adhesion. Step four is transmigration and chemotaxis. Step five is phagocytosis which involves consumption of pathogens or necrotic tissue. This process is enhanced by opsonins ____ and _____. The way by which phagocytosis occurs is that pseudopods from the leukocytes extend to form phagosomes. The phagosomes are internalized and merged with lysosomes to form phagolysosomes
IgG; C3b
Protein trafficking defect characterized by impaired phagolysosome formation; clinical features include increased risk of pyogenic infection, neutropenia, giant granules in leukocytes, defective primary hemostasis, albinism, and peripheral neuropathy
Chediak-Higashi syndrome
[can be thought of as a microtubule defect]
Inheritance of Chediak Higashi syndrome
Autosomal recessive
Destruction of phagocytosed material occurs by one of two mechanisms: oxygen-dependent or oxygen-independent. The oxygen-dependent mechanism is most effective. What is this mechanism?
HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes
[generation of HOCl occurs by the following: O2 is converted to O2* by NADPH oxidase — this is the oxidative burst! O2* is then converted to H2O2 by SOD. H2O2 is then converted to HOCl by MPO]
Disease characterized by poor O2-dependent killing due to NADPH oxidase defect
Chronic granulomatous disease
Inheritance of chronic granulomatous disease
X-linked or autosomal recessive
Key type of bacteria that those with chronic granulomatous disease are at risk for
Catalase-positive organisms! Most bacteria naturally produce a little bit of H2O2, so we can still generate HOCl using that, so CGD pts don’t have a problem with those. Catalase destroys H2O2, so catalase-producing organisms.
Important catalase-positive organisms to be aware of include: **Pseudomonas cepacia** S. aureus S. marcescens Nocardia Aspergillus
Test used to screen for chronic granulomatous disease
Nitroblue tetrazolium test
Turns blue if NADPH oxidase can convert O2 to O2*. Remains colorless if NADPH oxidase is defective
[allows you to differentiate from MPO deficiency, which would have a negative NBT test]
_____ deficiency results in defective conversion of H2O2 to HOCl*. These pts are typically asymptomatic, but are considered at increased risk for ____ infections
MPO; candida
The 2 ways in which organisms are killed after phagocytosis are O2-dependent killing and O2-independent killing (less effective). What is the mechanism of O2-independent killing?
Occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme and major basic protein)
Neutrophils undergo _____ and disappear within 24 hours after resolution of inflammatory stimulus
Apoptosis
What cell type predominates after neutrophils (i.e., peaks 2-3 days after inflammation begins)?
Macrophages
[derived from monocytes in the blood; arrive via margination, rolling, adhesion, and transmigration sequence identical to neutrophils. They then ingest via phagocytosis and destroy phagocytosed material using enzymes (lysozyme!) in the secondary granules]
Macrophages are responsible for managing next steps in acute inflammatory process. They promote resolution and healing via _____ and _____. They can allow continued acute inflammation via _____. They are also involved in abscess formation and chronic inflammation
IL-10; TGF-B; IL-8
Chronic inflammation is characterized by lymphocytes and plasma cells in tissues. It is a delayed response, but more specific (adaptive immunity). Stimuli for chronic inflammation include persistent infection (most common), infection with viruses, mycobacteria, parasites, and fungi, autoimmune disease, foreign material, and some cancers. Lymphocytes can be divided into T cells and B cells. Describe basic development of T cells
T cells form in the bone marrow from T cell progenitors
Further develop in thymus where TCR undergoes rearrangement. Progenitor T cells become CD4+ helper T cells or CD8+ cytotoxic T cells
T cells use TCR complex for antigen surveillance. The TCR complex recognizes antigens presented on MHC. What is the difference between MHC recognized by CD4 vs. CD8?
CD4+ T cells recognize MHC class II
CD8+ T cells recognize MHC class I
Activation of T cells requires 2 things: binding of antigen/MHC complex and additional 2nd signal. Describe these 2 events in the context of CD4+ T-cell activation
EXTRACELLULAR antigen is phagocytosed, processed, and presented via MHC class II (APCs — macrophages, dendritic cells, B cells)
B7 on APC binds CD28 on CD4+ T cells, providing the 2nd activation signal
CD4+ T-cells are divided into what 2 subtypes and their major products?
Th1 — secrete IL-2 and IFN-y
Th2 — secrete IL-4, IL-5, and IL-10
Major functions of IL-2 and IFN-y produced by Th1 CD4+ T-cells
IL-2 = T-cell growth factor and CD8+ T cell activator
IFN-y = macrophage activation
Major functions of IL-4, IL-5, and IL-10 secreted by Th2 CD4+ T-cells
IL-4 = class switching to IgG and IgE
IL-5 = eosinophil chemotaxis and activation, matruation of B cells to plasma cells, and class switching to IgA
IL-10 = inhibits Th1 phenotype
Activation of T cells requires 2 things: binding of antigen/MHC complex and additional 2nd signal. Describe these 2 events in the context of CD8+ T-cell activation
Intracellular antigen is processed and presented on MHC I
IL-2 from CD4+ Th1 cell provides 2nd activation signal
CD8+ T cells mediate cell killing by secretion of ____ and ____ — inducing apoptosis of target cell. This is mediated by expression of _____, which binds ____ on target cell activating apoptosis
Perforins; granzyme; FasL; Fas
Describe general development of B lymphocytes
Immature B cells are produced in bone marrow
Undergo Ig rearrangement to become naive B cells that express surface IgM and IgD
Mechanisms for B cell activation
Antigen binding surface IgM or IgD (becomes Ab-secreting plasma cell)
B-cell antigen presentation to CD4+ helper T cells via MHC II; CD40 receptor on B cel binds CD40L on helper T cell providing 2nd activation signal
One way in which B-cell activation occurs is B-cell antigen presentation to CD4+ helper T cells via MHC II; CD40 receptor on B cel binds CD40L on helper T cell providing 2nd activation signal. The helper T cell then secretes IL-4 and IL-5 which serve what purpose?
IL-4 and IL-5 mediate B-cell isotype switching, hypermutation, and maturation to plasma cells
A subtype of chronic inflammation is granulomatous inflammation. This is characterized by formation of a granuloma. The key cell of a granuloma is a(n) _____ _____ surrounded by giant cells and a rim of lymphocytes. Granulomas are divided into noncaseating and caseating subtypes
Epithelioid histiocyte (macrophages with abundant pink cytoplasm)
Noncaseating granulomas lack central necrosis. What are some clinical scenarios in which you see noncaseating granulomas?
Reaction to foreign material Sarcoidosis Beryllium exposure Crohn disease Cat scratch disease (Bartonella henselae)
[Note cat scratch disease shows stellate granulomas, usually in neck]
Caseating granulomas exhibit central necrosis. These are characteristic of what 2 clinical scenarios?
Tuberculosis infections
Fungal infections
[AFB stain looks for TB, GMS stain looks for fungus]
Steps involved in granuloma formation
- Macrophages present antigen via MHC II to CD4 T cells
- Macrophages secrete IL-12, inducing CD4 cells to differentiate into Th1 subtype
- Th1 cells secrete IFN-y, which converts macrophages to epithelioid histiocytes and giant cells
[Note — these steps are the same for caseating and noncaseating granuloma formation]
DiGeorge syndrome results from developmental failure of the ____________________ due to a ____ microdeletion
3rd and 4th pharyngeal pouches; 22q11
Clinical presentation of DiGeorge Syndrome
T-cell deficiency (lack of thymus)
Hypocalcemia (lack of parathyroids)
Abnormalities of heart, great vessels, and face
Severe combined immunodeficiency (SCID) involves defective cell-mediated and humoral immunity, characterized by susceptibility to fungal, viral, bacterial, and protozoal infections including opportunistic infections and live vaccines. What are the 3 major etiologies of SCID?
Cytokine receptor defects
Adenosine deaminase deficiency
MHC class II deficiency
Treatment of SCID pts
Sterile isolation
Stem cell transplant
Immunodeficiency characterized by complete lack of immunoglobulin due to disordered B-cell maturation, so naive B cells cannot become plasma cells
X-linked agammaglobulinemia
Genetic basis for X-linked agammaglobulinemia
Mutation in bruton tyrosine kinase (BTK)
Clinical presentation of X-linked agammaglobulinemia including age at presentation, types of infections seen, and considerations regarding vaccination
Presents after 6 months of life
Recurrent bacterial, enterovirus, and Giardia infections
Live vaccines (e.g., polio) must be avoided
[enterovirus and Giardia d/t lack of IgA protection of mucosal surface of the gut]
Common variable immunodeficiency (CVID) is characterized by low immunoglobulin due to B-cell or helper T-cell defects. What complications are these pts at risk for in childhood vs. adulthood?
Increased risk for bacterial, enterovirus, and Giardia infections (usually in late childhood)
Increased risk for autoimmune disease and lymphoma (usually later into adulthood)
What is the most common single Ig deficiency?
IgA deficiency — characterized by low serum and mucosal IgA leading to increased risk for mucosal infections, especially viral
In which GI disease is there a high incidence of IgA deficiency?
Celiac disease
Hyper-IgM syndrome is characterized by elevated IgM. What causes this condition?
Mutated CD40L or CD40 receptor
Thus the second signal cannot be delivered to the helper T cell during B cell activation — so cytokines necessary for Ig class switching are not produced. Low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites.
Triad associated with Wiskott-Aldrich syndrome
Thrombocytopenia
Eczema
Recurrent infections (defective humoral and cellular immunity)
Inheritence and genetic basis for Wiskott Aldrich syndrome
X-linked
Mutation in WASP gene
A complement deficiency affecting anything from C5 to C9 increases the risk for ______ infection
Neisseria
Consequence of C1 inhibitor deficiency
Hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal surfaces
Autoimmune disease results from a loss of self-tolerance. Where is central vs. peripheral tolerance usually generated?
Central occurs in generative organs: Thymus or bone marrow
Peripheral occurs in peripheral tissues (via anergy or apoptosis)
[note: negative selection in the medulla of the thymus removes self-reactive CD4 or CD8 lymphocytes by apoptosis prior to release of naive mature lymphocytes into circulation. Central tolerance in bone marrow allows the opportunity for receptor editing, followed by apoptosis if B cell is still self-reactive]
Autoimmune polyendocrine syndrome is associated with a _____ mutation that results in a breakdown in central tolerance, leading to hypoparathyroidism, adrenal failure, and recurrent candida infections
AIRE
[transcription factor in thymic medullary epithelial cells required to present self antigen to naive lymphocytes to check for tolerance]
What is autoimmune lymphoproliferative syndrome (ALPS) and how does it affect peripheral tolerance?
Mutations in Fas (CD95) apoptosis pathway — can’t undergo apoptosis in the periphery which eventually allows the survival of self-reactive lymphocytes
[may present with anemia or thrombocytopenia due to IgG against pts blood cells, generalized LAD, HSM, lymphoma]
Immunophenotype of regulatory T cells
CD4+ CD25+ FoxP3+
[CD25 is IL-2R]
2 types of mutations affecting regulatory T cells and their effects
CD25 polymorphisms — autoimmunity (e.g., multiple sclerosis and type 1 DM)
FOXP3 mutations — IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, x-linked)
Autoimmune disorders are more common in women and classically affect women of childbearing age, reflecting possible role of estrogen in pathogenesis.
Autoimmune disorders are also thought to involve environmental triggers in genetically susceptible individuals, evidenced by increased incidence in twins. There is an association with ____ subtypes and ____ polymorphisms. Triggers lead to bystander activation or molecular mimicry
HLA; PTPN22
[note: strongest association with HLA subtypes is HLA B27 and its association with ankylosing spondylitis]
Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease of which flares and remissions are common. SLE is often associated with nonspecific findings like fever, weight loss, fatigue, LAD, and Raynaud. What are the clinical features more specific to SLE?
Malar “butterfly” rash or discoid rash, especially upon sun exposure
Oral or nasopharyngeal ulcers
Arthritis
Serositis
Psychosis or seizures
Renal damage — diffuse proliferative glomerulonephritis (most common; type of nephritic syndrome), membranous glomerulonephritis (nephrotic syndrome)
Anemia, thrombocytopenia, or leukopenia (this is due to type II HSR, while lupus itself is type III HSR)
Libman-Sacks endocarditis — vegetations on BOTH sides of the valve
[only need 4 of the more specific criteria to make dx]
Pt populations most affected by SLE
Tends to affect middle aged females (10:1 F/M); More common in African Americans and Hispanics
Female bias is less dramatic in children and older adults
Pathogenesis and lab results suggestive of SLE
Antigen-antibody complex deposition in multiple tissues [Type III HSR]
Antibodies are often directed against host nuclear material. Activation of complement damages tissues (labs: decreased CH50, decreased C3, decreased C4)
Thus pts with early complement deficiencies (C1q, C4, C2) are associated with developing SLE because these are required for initiating clearance of the Ag-Ab complexes
What is the significance of looking for ANA antibody in pts suspected of having SLE? What is a better test?
ANA antibody is sensitive but not specific — used to screen for SLE
Anti-dsDNA and anti-Sm are specific to SLE
Antiphospholipid antibodies can also be tested
Which antibody associated with SLE can be used to assess prognosis because it predicts renal involvement (common cause of death in SLE)?
Anti-dsDNA
Antiphospholipid antibodies are autoantibodies against proteins bound to phospholipids. What are the 3 major antiphospholipid antibodies?
Anticardiolipin (associated with false positive VDRL and RPR for syphilis)
Lupus anticoagulant (associated with falsely elevated PTT)
Anti-b2-glycoprotein I
What is antiphospholipid antibody syndrome?
Antiphospholipid antibody plus hypercoagulable state (note this is paradoxical because PTT will appear to be prolonged)
Prone to deep vein, hepatic vein, placental, and cerebral thrombosis
Requires lifelong anticoagulation
_____ antibody is characteristic of drug-induced SLE
Antihistone
Drug-induced SLE usually goes into remission when drug is removed. CNS and renal involvement are rare in these cases, and they are considered ANA+ to anti-histone antibody. What 3 drugs are commonly associated with drug-induced SLE?
Hydralazine
Procainamide
Isoniazid
Treatment for SLE
Avoid sunlight
Glucocorticoids (flares)
Other immunosuppressive agents
Prognosis of SLE and common causes of death
Px is good with >90% 5-year survival
Renal failure and infection are most common causes of death; accelerated coronary atherosclerosis (late)
Autoimmune destruction of lacrimal and salivary glands due to lymphocyte-mediated damage with fibrosis
Sjogren syndrome
What type of HSR is Sjogren syndrome?
Type IV HSR — because it is lymphocyte-mediated damage
Classic presentation of Sjogren syndrome
Dry eyes, dry mouth, and recurrent dental caries in older woman
Pts may complain that they can’t chew a cracker and feel like they have dirt in their eyes
Extraglandular manifestations are common — Lymphocytic sialadenitis seen on bx of lip [this is very important for dx of Sjogrens!]
Sjogren’s syndrome can be primary, or associated with another autoimmune disorder. It is commonly associated with ____ _____
Rheumatoid arthritis
[Note: rheumatoid factor is often present, even in primary disease where rheumatoid arthritis is absent]
Sjogrens is characterized by ANA and ___________, classically _____ and _____
Anti-ribonucleoprotein; Anti-SSA; Anti-SSB
Presence of Anti-SSA and Anti-SSB antibodies in Sjogren’s syndrome is associated with extraglandular manifestations, risk of neonatal ____, and congenital _____ _____. These antibodies are also seen in a subset of _____ patients, and it is important to screen pregnant women with this condition
lupus; Heart block; SLE
Complication of Sjogrens syndrome that presents as unilateral enlargement of parotid gland late in disease course
B-cell lymphoma
Autoimmune disorder more common in middle-aged females presenting with sclerosis of the skin and visceral organs
Systemic sclerosis (scleroderma)
Pathogenesis of systemic sclerosis involves _____ activation leading to deposition of ______
Fibroblast; collagen
[this leads to autoimmune damage to mesenchyme, endothelial dysfunction, perivascular fibrosis, and organ damage]
Systemic sclerosis can be divided into a limited type and a diffuse type. In the limited type there is limited skin with late visceral involvement. The prototype of this is CREST syndrome — what are the components of this syndrome?
Calcinosis/anti-Centromere antibodies
Raynaud phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias of skin
Systemic sclerosis can be divided into a limited type and a diffuse type. The diffuse type diffusely involves the skin with early visceral involvement. What aspects of viscera are typically involved and what Abs are characteristically seen?
Vessels, GI tract, lungs, kidneys, heart (but any organ can be involved)
DNA topoisomerase I antibodies
[note: GI tract is most commonly involved viscera. Lung involvement is most common cause of death — due to pulmonary hypertension or interstitial fibrosis; kidney is second most common cause of death — due to scleroderma renal crisis]
Mixed connective tissue disease involves autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis. What antibodies are seen in this condition?
ANA with serum antibodies against U1 ribonucleoprotein (RNP)
