Immunology Flashcards
What phagocytes cells circulate
Neutrophils and monocytes
What phagocytes are in tissues
Macrophages and langerhans
What are the dominant cells of destruction of microbes and other offending agents
Macrophages
Dendrite
In epithelial, lymphoid organs and most tissues
Capture protein antigens and display peptides for T cells
*stimulate secretion of cytokines and involved in the initiation of innate immune responses
Nk cell
Early protections gainst viruses and intracellular bacteria
Plasma proteins
Complement
Mannose binding lectin CRP that coat microbes OPSONINS
Lung surfactant to provide protection against inhaled microbes
PRR (pattern recognition receptor)
Recognize aspects of microbes or DAMP
Damp
Damage associated molecular pattern released by dying or damaged cells
Danger signals/alarmin
Where are PRR
Plasma membrane for extracellular
Endosomes for digested
Cytosolic for cytoplasm
What are the four innate immune receptors
TLR(plasma membrane and endosomes vesicles), NOD like(cytosolic), C type lectin receptors, and RIG like receptors
TLR activation from microbial products
Activate transcription factors-
NF-KB and interferon regulatory factors
NFKB-stimulates synthesis and secretion of cytokines and adhesion molecules for recruitment and activation of leukocytes.
IRF-antiviral cytokines -type 1 interferons
If TLR lost
Serious immunodeficiency problems
NOD-like receptors (NLRs) when bind products of necrotic cells like uric acid and ATP, ion disturbances like k loss and some microbial products
Inflammasome which activates caspase 1 that cleaves a precursor form of il1 into its active form
Gain of function NLR
Periodic fever syndrome called autoinflammatory syndrome which is treated by an il1 antagnoist
NLR in gout
NLR inflammasome pathway plays a role int he innate immune system recognition of urate crystals and promoting the inflammation associated with gout.
Inflammasome pathway
Protein complex that recognizes products of dead cells and some microbes and induces the secreiton of biologically activated IL-1
NLR activates inflammasome which activates caspase 1 which cleaves pro-I1b into il-1B for it to be secreted from the cell
NLPR3
Sensor protein leucine rich
C type lectin receptors
Expressed not he plasma membrane of macrophages and dendritic cells
Detect fungal glucan and elicit inflammatory reactions to fungi
Rig like receptors
Cytosolic detect nuclei acids of viruses that replicate int he cytosolic of infected cells
Stimulate production of antiviral cytokines
Intracellular nuclei acids (viral RNA)
Gpcr
Neutrophils, macrophages, and msot leukocytes
Recognize bacterial peptides containing n-formylmethionyl (prokaryotes and mitochondria)
Mannose receptors
Recognize microbial sugars with terminal mannose residues and induce microbial phagocytes
Mannose is bacterial cell well constituent)
Type 1 interferons
Activate enzymes that degrade viral nuclei acids and inhibit viral replication to induce antiviral state
When does lymphocyte become not naive
When find antigen
How get lymphocyte diversity
Somatic recombination of genes hat encode the receptor proteins in thymus for T cells and bone marrow for B cells
For lymphocyte diversity how are gene segments recombined randomly
RAG1 and RAG2
RAG mutated
No mature lymphocytes
How tell if lymphocyte proliferation is polyclonal )non neoplastic) or monoclonal (neoplastic)
molecular assays using PCR
Bc each t or B cell and its colonial progeny have a unique DNA rearrangement (unique antigen receptor)
For lymphoma
TCR ab
Ab
Recognize MHC
CD3 and zeta chain-invariant, identical in all cells
TCR gamma delta
Peptides, lipids, small molecules, without assistance from MHC proteins
On epithelial surfaces (skin, GI and urogenital tracts)
NKT cell
Some have TCR that recognize MHC like molecule CD1
But this is adaptive immunity
T cell coactivator
CD28 on T cell interacts with cd80/86 (b7)
B cell receptor
IgM or igd
Activated B cell
Turns into plasma cells
Co receptors B cells
Iga and IgB (CD79a and CD79b)
0invariant for transduction
T cell and. Cell interaction
CD40L Cd40
HyperIgM syndrome
CR2 or CD21
This receptor can also be used by EBV to enter and infect B cells
Dendritic cells
APC for T cell responses
Located at the right place to capture antigens-under epithelial (langerhans in skin)-interstitial of all tissues where antigens may be produced
TLR and lectins
Recruited to T cell zones of lymphoid organs in response to microbes
Dendrites MHC
Lots of them needed for presenting antigens to and activating T cells
Dendritic follicular cells
Found in germinal centers of of lymphoid follicles in spleen and lymph nodes
Fc receptors for IgG and Receptors for c3b to trap antigens bound to antibodies or complement proteins
Present and select the highest addnity B cells
_ cells can activate macrophages and enhance their ability to kill ingested microbes
T
How macrophages phagocytes and destroy microbes
Opsonized by igg or c3b
NK cells what kill
Kill virus infected cells and tumor cells
How do nk cells kill
Azurophilic granules without prior exposure
Surface molecules of NK
CD16: an Fc receptor for IgG, lyse IgG coated cells in antibody dependent cell mediated cytotoxicity
Secrete ifny for macrophage activation
Antibody dependent cell mediated cytotoxicity
Nk cell kids and lyse IgG coated target cels
When nk cell kill
No MHC
What cytokines regulate nk cells
Il2, il15, stimulate proliferation
Il2 and il15->NK cells->il12->TH1->ifny->macrophage (classical activation)
Il12 activates killing and secretion of ifny
Innate lymphoid cells
New
Nk cells are first defined ILC
Early defense
HLA chromosome
6
MHC1 antigen binding
A1, a2 binding groove
A3 is nonpolymorphc and has a binding sitefor cd8
B2 microglobulin
Cytoplasm like viral and tumor antigens
Mhc2 binding (macrophages B cells dendritic cell)
A1, b1 binding groove
B2 binding site for cd4
Extracellular bacteria and soluble proteins
HLA inheritance
Codominantly from each parent
Everyone has different HLA HaplotypE
Transplant hard
Except identical twin
Cytokines that limit and terminate immune response
Tgfb and il10 and antiinflammatory
What cytokines stimulate hematopoietic
CSF
GM CSF and IL7
Treat RA
Tnf antagonists
Primary lymphoid organs
Thymus and bone marrow
Secondary lymphoid organs
Lymph nods, spleen, mucosal and cutaneous lymphoid tissues
Lymph nodes vs spleen
Nodes-lymph dendrites
Spleen-blood macrophages and dendrites
How does blood enter spleen
Sinusoids trapped in macrophages and dendrites
Mucosal lymphoid systems
Under epithelial of skin, GI and respiratory tracts
Antigens through breach of epithelium
Immmunization with a protein antigen
Microbial mimics called adjuvants are given with the antigen and these stimulate the innate immune response
TH1
Ifny is 12 —-> il2 ifny
Macrophage activation and stimulate IgG production
Intracellular microbes
Autoimmune disease, IBD< psoriasis, granulomatous inflammation
TH2
Il4->4, 5, 13
5-IgA class switch, eosinophils 4->igE class switching Il13-alternate macrophage activation (tissue repair and fibrosis)
Stimulates igE, activation of mast cells and eosinophils
Helminthis parasites
Allergies
TH17
TGFB, il6, 1, 23->IL17, 22
Recruits neutrophils and monocytes
Extracellular bacteria and fungi
Autoimmune disease, chronic inflammation, psoriasis, ms
T dependent humoral immunity-protein antigens
Require T cell help
B cell ingest protein display on mhc2
Helper T cell use cd40L to help class switch and affinity maturation
Ifny and il4->isotype switching
IgA
Mucosal epithelial
IgG
Transported across the placenta and immunity to newborn
IgE and eosinophils
Parasites
T independent humoral immunity
Non protein antigens
Polysaccharide and lipid antigens cant be recognized by T cells but have multiple identical antigenic determinants (epitomes) that are able to engage many antigen receptor molecules on each B cell and initiate process of B cell activation
NO IMMUNOGLOBULIN ISOTYPE SWITCHING AND AFFINITY MATURATION
Mainly igM
Type I hypersensitivity
IgE, TH2, mast, and other leukocytes
Il4-IgE and TH2
Il5-eosinophils
Il13-enhance IgE and stimulate mucus
Who gets immediate hypersensitivity type I
Presensitized
Immediate reaction type I
Vasodilation, vascular leakage, congestion, edema
Minutes after exposure and subsides in a few hours
Treat immediate type I
Epinephrine
Late phase type I
2-24 hours lasts for days
Allergic rhinitis and bronchial asthma
Eosinophils, neutrophils, basophils, monocytes, and cd4, tissue destruction
What cell dominates late phase type I
Eosinophils
Mast cells and basophils
Mast-tissue
Basophils-circulating counterpart
Stain mast cells
Blue
Activation mast cell
Cross link igE FceR1 receptors
C2a and c5a
IgE coated mast cells
Sensitized
MOA type I hypersensitivityq
Cd4 activated by a DC and release Il4, get TH2 and il4, 5, 13
4-IgE and TH2
50development and activation eosinophils
13-igE enhance and mucus,
TH2, mast, and epithelial cells make chemokine attract th2 and other leukocytes which sensitize mast cells so the next time mast cells exposed to antigen get IgE crosslinks and activation
Treat anaphylaxis
Epinephrine
What are preformed mast cell mediators
Vasoactive amine: histamine
Enzymes:neutral proteases (Chumash trypatase) and acid hydrolase)
Histamine
Sm contraction, vascular permeability, and increased secretion
Epinephrine counteracts histamine
A1 agonist, beta 1 agonist, beta 2 agonist
Proteoglycans
Heparin; anticoagulant
Chondriotin sulfate
Lipid mast cell mediator
Arachidonic acid derived
Reactions in mast cell membranes lead to activation of phospholipase a2, converts membrane phospholipids to aa which is converted to leukotrienes and prostaglandins
Leukotriene c4 and d4
Most potent vasoactive and spasmogenic agents
Leukotriene b4
Highly chemotactic for neutrophils, eosinophils, and monocytes
Prostagladin D2
Abundant, causes intense bronchospasm and increased mucus secretion
PAF
Platelet aggregation, release of histamine, bronchospasm, increased vascular permeability and vasodilation.
Not derived from aa
What does mast cell secrete
Tnf il1 and chemokine
Leukocyte recruitment , epithelial damag,
Il4-amplifies th2 Response
What mediators are responsible for immediate hypersensitivity
Preformed0histamine, neutral proteases, proteoglycans
Secondary mediators-leukotrienes, prostagladin D2, PAF
Cytokines-tnf il1, il4 chemokine
What mediators and responsible for the intense immediate reactions characterized by edema , mucus secretions and smooth muscle spasm
Histamine and leukotrienes
Which mediators set the stage for the late phase response by recruiting additional leukocytes
Cytokines and chemokines
Late phase type I
Leukocytes (eosinophils) don need additional triggering antigen
Major cause of symptoms
Eosinophils release what
Proeolytic enzymes, major basic protein, eosinophil cationic protein
Treat late phase
Anti inflammatory
When use antihistamine
Only intermediate reaction
Most potent eosinophil activating factor
Il5
Chemotactic for eosinophils
Eotaxin
Atopy genetic
More IgE and IL4 producing TH2 cells
Why allergies more in developed countries
Exposure to pollutants trigger
Non atopic allergy
No th2 or ige
Mast cells abnormally sensitive to activation by nonimmune stimuli
Systemic anaphylaxis
Minutes, vascular shock, widespread edema, and difficulty in breathing
Sensitized individuals
Type II
IgM and IgG promote lysis or phagocytosis and injure tissue
Complement activation
Antibody dependent cellular cytotoxicity
Antibody dependent cellular cytotoxicity
cells coated with IgG antibody are killed by a variety of effector cells, mainly NK cells and macrophages, and cell lysis occurs without phagocytosis
MOA: When antibody is directed at a parasitic infection, there if Fc receptor-mediate inflammation and phagocytosis, characteristic of ADCC. IgG and IgE antibodies bearing Fc receptors coat the parasite. Macrophages, natural killer cells, and neutrophils can then recognize the Fc receptor and destroy the antibody-coated target cells.
contribution of ADCC to hypersensitivity diseases is uncertain
When get antibody mediated cell destruction and phagocytosis in disease occurs in what situation
Transfusion, hemolytic disease of newborn , autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia
Transduction reactions
cells from an incompatible donor react with and are opsonized by preformed antibody in the host.
Pink-colored urine == hemolysis; RBCs are prone to hemolysis by antibody mediated activation of complement
** this was a CIS question
Hemolytic disease of new born
(erythroblastosis fetalis): maternal IgG anti-erythrocyte antibodies cross the placenta and cause destruction of fetal red cells
Autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia
a: individuals produce antibodies to their own blood cells, which are then destroyed
Antibody mediated inflammation in disease
when antibodies deposit in fixed tissue (i.e. basement membrane and ECM), tissue injury is due to inflammation
deposited antibodies activate complement –> C3a and C5a –> leukocytes –> lysosomal enzymes (i.e. proteases) –> ROS
Responsible for tissue injury in some forms of:
Glomerulonephritis
Vascular rejection in organ grafts
Others
Antibody mediated cellular dysfunction in disease
antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation
Myasthenia gravis
Antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles act as antagonists block neuromuscular transmission → muscle weakness
Graves disease
Antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells act as agonists stimulate the cells → hyperthyroidism
^^ these are referred to as “anti-receptor
Type III
IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in vessel walls and induce inflammation (vasculitis
How type III antigen antibody complies
Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition
Typically in vessel walls (vasculitis
Immune complex mediated disease involve what
Kidney (glomerulonephritis)
Joints (arthritis)
^^ organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and tend to deposit
Small blood vessels (vasculitis
Systemic immune complex disease
Immune complex-mediated diseases tend to be systemic
Acute Serum Sickness == prototype of a systemic immune complex disease
this happens when you are given anti-serum derived from animal sources – single large exposure to antigen
i.e. serum from immunized horses was used for protection against diphtheria
i.e. rattlesnake antidote
patient receives antibodies from other individuals or species
lesions tend to resolve as a result of catabolism of the immune complexes
chronic serum sickness: results from repeated or prolonged exposure to an antigen
Systemic Lupus Erythematous: associated with persistent antibody responses to autoantigens
Pathogenesis systemic immune complex disease
formation of immune complexes
introduction of protein antigen –> host response to make antibodies
~1 week after introduction, antibodies are secreted into the blood where they react with antigen that is still present –> antigen/antibody complex
deposition of immune complexes
circulating antigen/antibody complex are deposited in various tissue
complexes that are of medium size and formed in slight antigen excess are most pathogenic
inflammation and tissue injury
after deposition –> acute inflammatory reaction
~10 days s/p antigen introduction
fever, urticaria, arthralgia (joint pain), lymphadenopathy, and proteinuria
Local immune complex disease (Arthur’s resection)
Arthus Reaction: localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin
produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against the antigen
As the antigen diffuses into the vascular wall, it binds the preformed antibody and large immune complexes are formed locally
Immune complex disease pathogenesis
Complement-fixing antibodies (i.e., IgG and IgM) Induce the pathologic lesions of immune complex disorders
Complement proteins can be detected at the site of injury
Consumption of complement proteins during active phase → decreased serum levels of C3
serum C3 levels can be used to monitor disease activity
The principal morphologic manifestation of immune complex injury is acute vasculitis, associated with necrosis of the vessel wall and intense neutrophilic infiltration
appear as fibrinoid necrosis (smudgy, eosinophilic area of tissue destruction of vessel walls)
when deposited in the kidney, complexes can be seen on
immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement
electron microscopy as electron-dense deposits along the glomerular basement membrane
Type IV
sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of tissue injury
Caused by inflammation resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells
Cd4 mediated inflammation
Activation of CD4+ T Cells
Naive CD4+ T cells recognize peptides displayed by dendritic cells and secrete IL-2 to stimulate proliferation of antigen-responsive T cells
Antigen-stimulated T cells differentiate to TH1 or TH17 cells based on the cytokines produced by APCs
IL-12 –> TH1 –> IFN-γ –> more TH1
IL-1, IL-6, and IL-23 –> TH17
Responses of Differentiated Effector T Cells
Repeat exposure to antigen causes TH1 cells secrete cytokines (mainly IFN-γ) which are responsible for many of the manifestations of a delayed type hypersensitivity
IFN-γ-activated (“classically”) macrophages:
Enhanced ability to phagocytose and kill microorganisms
Express more class II MHC molecules on the surface
Secrete pro-inflammatory TNF, IL-1, and chemokines
Produce more IL-12 which causes an amplified TH1 response
Activated macrophages eliminate the offending antigen, but if activation is sustained, continued inflammation leads to tissue injury
Activated TH17 cells secrete IL-17, IL-22, chemokines, and other cytokines
Recruit neutrophils and monocytes to the reaction (i.e. pro-inflammatory)
Produce IL-21, which amplifies the TH17 response
Tuberculin reaction
purified protein derivative (PPD, also called tuberculin), a protein- containing antigen of the tubercle bacillus, is intracutaneously injected into previously immunized individuals
Previously sensitized individuals will have reddening and induration of the site appear in 8 to 12 hours and peaks at 24 to 72 hours.
Clinical Morphological Changes
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules –> perivascular “cuffing”
in fully developed lesions, the venules show marked endothelial hypertrophy, reflecting cytokine mediated endothelial activation
Tuberculous infection
Persistent or nondegradable antigens (i.e. tubercle bacilli colonizing the lungs or other tissues).
Infiltrate is dominated by macrophages after 2-3 weeks.
Sustained activation causes macrophages undergo a morphologic transformation into epithelioid cells, large epithelium-like cells with abundant cytoplasm.
A microscopic aggregation of the epithelioid cells, usually surrounded by lymphocytes, is called a granuloma.
Granulomatous inflammation
Associated with strong TH1-cell activation and high-level production of cytokines such as IFN-γ.
can also be caused by indigestible foreign bodies, which activate macrophages, but don’t elicit an adaptive immune response
Contact dermatitis
vesicular dermatitis
thought that the environmental chemical (e.g. urushiol from poison ivy, nickel) binds to and structurally modifies self-proteins and peptides derived from these modified self-proteins are recognized by T cells that then elicit the reaction
same mechanism is responsible for most drug reactions: drug alters self-proteins, including MHC molecules, and the “neoantigens” are recognized as foreign by T cells, leading to cytokine production and inflammation
manifest as skin rashes
Cd8 mediated cytotoxicity
T cell–mediated diseases.
e.g. Type 1 diabetes or graft rejection after organ transplantation.
Plays a role in reactions against viruses.
Some cases it is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis).
activated CTLs express Fas ligand
Involved in killing tumor cells.
Tumor-associated antigens are presented on the cell surface
Mnemonics
I: Allergic Anaphylaxis and Atopy First and Fast, like anaphylaxis II: antiBody cyTWOtoxic (antibody mediated) III: immune Complex three makes a complex IV: Delayed Contact Dermatitis
Dysbiosis
An alteration of the body’s microbial community that decreases the pop of good bacteria and allows the bad bacteria to take over.
Is implicated in:
IBD, allergy, and autoimmune disease
Three requirements of autoimmune disease
Presence of an immune reaction that is specific for some self-antigen or self-tissue
The reaction is not secondary to tissue damage, but rather it is the thing that is causing the tissue damage
absence of another well-defined cause of disease
Wire mutation
Autoimmune polyendocrinopathy
Immunologic intolerance
Central tolerance T cell
Negative selection of the T cells that are developing in the thymus.
Some of the T cells become TREG cells instead of being killed off to help protect against autoimmunity
B cell central tolerance
Negative selection of developing B cells in the bone marrow.
Don’t automatically die if they are self-reactive, they can undergo receptor editing to try again.
They will die if the receptor editing doesn’t work though
Peripheral tolerance anergy
Lymphocytes that recognize self-antigens are rendered functionally unresponsive if they do not receive costimulation – anergy.
T cells that recognize self-antigens receive inhibitory signals from receptors that are structurally homologous to CD28
CTLA-4: like CD28, CTLA-4 binds to B7 molecules but does not activate signaling pathways
CLA-4 has higher affinity for B7 than CD28 does – CTLA-4 is preferentially engaged when B7 levels are low
there is low level constitutive expression of B7 on resting dendritic cells in normal tissues
there is low level of expression of B7 on APCs that are presenting self-antigen
microbial products elicit innate immune response that increases expression of B7 on APCs
PD-1: binds to two ligands that are expressed on a wide variety of cells
mice lacking CTLA-4 and PD-1 develop autoimmune disorders
Happens when an antigen is presented to the T cells by an APC in the absence of costimulation
This pathway is used by some viruses and tumors to evade immune attack.
B cells can have the same thing happen too if they don’t get signals from the specific T helper cell for that antigen
Peripheral tolerance treg
TREG cells function to prevent immune reactions against self-antigens.
anti-inflammatory functions of TREG cells: secrete IL-10 and TGF-β, express CTLA-4
TREG cells are defined by CD4+/CD25+/high levels of α chain of IL-2 receptor/FOXP3+
mutations in FOXP3 == IPEX (immune dysregulation, polyendocinopathy, enteropathy, X-linked) syndrome
IL-2 is essential for the maintenance of TREG cells
TREG cells play a role in acceptance/tolerance of a fetus (which is 50% foreign)
The fetus displays antigens that are foreign and need to be tolerated.
Placentation evolved simultaneously with ability to stably express Foxp3 transcription factor
Mice: fetal antigens induce long-lived Foxp3+ TREG cells
depletion of TREG cells may lead to recurrent spontaneous abortions
Peripheral tolerance deletion/apoptosis
self-reactive T-cells may express pro-apoptotic member of the BCL family (Bim) without anti-apoptotic members of the family like Bcl-2 or Bcl-x (whose induction requires the full set of signals for lymphocyte activation)
unopposed Bim triggers apoptosis (intrinsic/mitochondrial pathway)
self-reactive T-cells may also undergo extrinsic pathway apoptosis via Fas/FasL pathway
if self-antigens engage antigen receptors of self-reactive T-cells, Fas and FasL are co-expressed and lead to apoptosis
self-reactive B cells may also be deleted by FasL on T cells engaging Fas on B cells
Autoimmune LymphoProliferative Syndrome (ALPS): disease caused by mutations in the FAS gene
Immune privilege sites
Testis, eye brain
No communicate blood/lymph
Post traumatic orchitis and uveitis
self-antigens in these tissues fail to elicit immune responses and are essentially ignored by the immune system
If the tissues are damaged or infected and the antigens are released, there can be prolonged tissue inflammation and injury.
post-traumatic orchitis and uveitis
PTPN22
rheumatoid arthritis, type 1 diabetes, and several other autoimmune disorders
encodes a protein tyrosine phosphatase
said to be the gene most frequently implicated in autoimmunity
LOF mutation –> excessive lymphocyte activation
NOD2
Crohn disease
cytoplasmic sensor of microbes that is expressed in intestinal epithelial and other cells
disease associated variant is ineffective at sensing gut microbes, including commensal bacteria, resulting in entry of and chronic inflammatory responses against these normally well-tolerated organisms
IL2 receptor (CD25) and il17 receptor a chain
multiple sclerosis and other autoimmune diseases
these cytokines may control the maintenance of TREG cells
Molecular mimicry
he microbial antigen looks like a self-peptide. Immune response against the microbial antigens may active self-reactive T-cells
Ex: rheumatic heart disease
antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis.
Some viruses like EBV and HIV cause polyclonal B cell activation that may cause production of autoantibodies
Ok
By what mechanism is centra tolerance acheived
Apoptosis of self reactive lymphocytes
Mechanism of peripheral tolerance
Treg, anergy, apoptosis ,
Infections reduce the incidence of disease
This may be due to infections promoting low level IL-2 production which is essential for maintaining TREG cells
What causes inflammatory disease
TH1 and 17
Good pasture
A nti-basement membrane, anti- type IV collagen
Antiphospholipis syndrome, SLE
A nticardiolipin, anti-β2-glycoprotein “lupus anticoagulant
SLE
Antiphospholipid Syndrome, SLE == anticardiolipin, anti-β2-glycoprotein “lupus anticoagulant”
SLE == anti-dsDNA, anti-Sm
drug-induced SLE == anti-histone antibodies
Jorgen
anti-SS-A, anti-SS-B
Mixed CT disease
= anti-U1-ribonucleoprotein
Polymyositis/dermatomyositis
Anti-Jo-1
CREST
limited scleroderma (CREST syndrome) == anticentromeric antibody
Diffuse systemic scleroderma a
Anti dna topoisomerase
SLE
Affects Hispanic and African American women more than white men.
Involves multiple organs like the skin, joints, kidney, and serosal membranes – hence “systemic”
immune complex mediate glomerulonephritis
There are many autoantibodies, particularly antinuclear antibodies.
Injury is caused by deposition of immune complexes and binding of antibodies to various cells and tissues.
Type III Hypersensitivity
Can be acute or insidious
Typically chronic, remitting and relapsing
The clinical presentation is highly variable
classic picture of SLE == erythematous malar facial skin rash and renal failure with proteinuria and hematuria from immune complex deposition in the glomeruli.
hallmark of SLE == production of autoantibodies
Antinuclear antibodies
Directed against nuclear antigens. 4 categories: antibodies to DNA antibodies to histones antibodies to non-histone proteins bound to RNA antibodies to nucleolar antigens
Detecting Ana
Indirect immunofluorescence
There are 4 basic patterns of immunofluorescence.
Diffuse: antibodies to chromatin, histones, nucleosomes, and dsDNA
common in SLE
Anti-centromeric: seen in systemic sclerosis, Sjogren syndrome, and other diseases
Rim/Peripheral: antibodies to dsDNA and nuclear envelope proteins
Speckled: antibodies to non-DNA (i.e. Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens)
most commonly observed == least specific
nucleolar: antibodies to RNA and nuclear proteins
systemic sclerosis
Centromeric: patients with systemic sclerosis often contain antibodies specific for centrosomes
antibodies to double-stranded DNA and the so called Smith (Sm) antigen are virtually diagnostic of SLE
Antiphospholipid antibody
30-40% of lupus patients
directed against epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids
prothrombin, annexin V, β2-glycoprotein I, protein S, and protein C
May cause a false-positive test result (VDRL) for syphilis.
antibodies against the phospholipid-β2-glycoprotein complex also bind to cardiolipin antigen used in syphilis serology
Can interfere with clotting tests such as PTT, which makes it look like there is a Lupus anticoagulant, but really patients with these antibodies are in a hypercoagulable state.
elevated/prolonged PTT but hypercoag
Etiology SLE
Failure of the mechanisms that maintain self-tolerance.
Cause in unknown, but genetics and environment are likely
Genetics sle
Evidence
Increased risk of SLE in family members of patients with SLE.
Higher rate of concordance (>20%) in monozygotic twins than in dizygotic twins.
Specific alleles of HLA-DQ have been linked to production of anti-dsDNA, anti-Sm, and anti-phospholipid antibodies.
Some patients have inherited deficiencies of early complement components (i.e. C2, C4, and C1q) which leads to impaired removal of circulating immune complexes by mononuclear phagocytes
Knockout mice for C4 are prone to develop lupus-like autoimmunity
Many MHC and non-MHC genes are implicated.
There are susceptibility loci that encode proteins involved in lymphocyte signaling and interferon responses, but each loci is a small risk.
Immune sle
failure of self-tolerance in B cells –> autoantibodies
CD4+ T-cells specific for nucleosomal antigens escape tolerance
autoantibodies in SLE show characteristic of T-cell dependent
increased number of follicular helper T cells have been detected in the blood of SLE patients
TLR engagement may provide second signal –> B cell activation -> increased production of autoantibodies
Type I Interferons: activate lymphocytes in SLE
high levels of circulating Type I Interferons and a molecular signature in blood cells suggesting exposure to these cytokines has been reported in SLE patients and correlates with disease severity
Env SLE
UV light exacerbates the disease in many patients.
Can induce apoptosis and alter the DNA so that it is immunogenic, perhaps due to enhanced recognition by TLRs
Stimulates keratinocytes to produce IL-1 and thus modulates the immune response
Gender bias
Sex hormones and genes on the X chromosome independent of hormone effects
Drugs can induce an SLE-like response in humans
Hydralazine, procainamide, and D-penicillamine
symptoms resolve once drug is withdrawn
Microbiome
autoantibodies specific for RBCs, white cells, and platelets –> hemolytic anemia, leukopenia, and thrombocytopenia
LE bodies: in tissue, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogenous; aka hematoxylin body
LE cell: readily seen when blood is agitated in vitro; LE cell is any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell
historical interest
Antiphospholipid antibody syndrome
elevated PTT but hypercoaguable state – “lupus anticoagulant”
recurrent spontaneous miscarriages and focal cerebral or ocular ischemia
in association to lupus == secondary antiphospholipid antibody syndrome
not associated with SLE == primary antiphospholipid antibody syndrome
Morphology SLE blood vessels
Blood vessels: acute necrotizing vasculitis involving capillaries, small arteries and arterioles.
characterized by fibrinoid deposits in the vessel walls
chronic stages: vessels undergo fibrous thickening with luminal narrowing
SLE CT/joints
Connective Tissue/Joints: non-erosive synovitis with little deformity (different than RA
Kidney sle
up to 50% of patients have clinically significant renal involvement due to immune complex deposition that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus
more probably have asymptomatic renal involvement
Both in situ formation and deposition of preformed circulating immune complexes.
kidney virtually always shows some evidence of renal involvement by EM and immunofluorescence
6 patterns of glomerular disease in SLE – not important here; comes up again in Renal II – not important there
Class I SLE
Minimal mesangial lupus nephritis.
immune complex deposition in the mesangium
Seen on EM or immunofluorescence only.
no structural changes identified by light microscopy – a lot like Minimal Change Disease
Least common
Class II SLE
mesangial proliferative lupus nephritis
Class III SLE
: focal lupus nephritis.
defined by involvement of <50% of all glomeruli
segmental or global involvement of the glomerulus
affected glomeruli == swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi; also often extracapillary proliferation associated with focal necrosis and crescent formation
Presentation spectrum: mild hematuria and proteinuria acute renal insufficiency
red cell casts in urine common when disease is active
Class IV SLE
diffuse lupus nephritis.
Most common and severe form of lupus
defined by involvement of >50% of all glomeruli
segmental or global involvement of the glomerulus
affected glomeruli == proliferation of endothelial, mesangial, and epithelial cells –> lateral crescents that fill Bowman’s Space
subendothelial immune complex deposits may create a circumferential thickening of the capillary wall, forming “wire loop” structures on light microscopy
hematuria, proteinuria, hypertension, mild to severe renal insufficiency
Class V SLE
V: membranous lupus nephritis
diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes usually accompanied by increased production of basement membrane-like material
severe proteinuria or nephrotic syndrome
Class VI SLE
: advanced sclerosing lupus nephritis
sclerosis of more than 90% of the glomeruli
End-stage renal disease
Skin sle
Characteristic “butterfly rash” in half of patients that is located on their face with the two wings being on their cheeks and maybe forehead
Can also have a similar rash on their extremities and trunk
urticaria, bullae, maculopapular lesions, and ulcerations also occur
Exposure to sunlight incites or accentuates the erythema
Histology:
involved areas show vacuolar degeneration of the basal layer of the epidermis
dermis: variable edema and perivascular inflammation
vasculitis with fibrinoid necrosis (affects vessels) may be prominent
Immunofluorescence: deposition of immunoglobulin and complement along the dermal-epidermal junction.
Can also be present in uninvolved skin
Also seen in scleroderma or dermatomyositis – sensitive but not specific
Pericarditis sle
and other serosal involvement in SLE
Inflammation of the serosal membranes may be acute, subacute, or chronic.
Acute: mesothelial surfaces are sometimes covered with fibrinous exudate.
Later: thickened, opaque, and coated with a shaggy fibrous tissue.
May lead to partial or total obliteration of the serosal cavity.
There may also be pericardial and pleural effusions.
Cardiovascular system sle
damage to any layer of the heart
Affects about half of patients and may not be symptomatic.
Myocarditis (inflammation of the myocardium) can lead to resting tachycardia and ECG abnormalities.
Coronary artery disease can lead to angina or MI.
especially prevalent in young patients with long-standing disease and those who have been treated with corticosteroids
Valve problems (mostly to mitral and aortic) can lead to stenosis and/or regurgitation.
Valvular (Libman-Sacks) endocarditis
Uncommon now due to the use of steroids.
also known as Nonbacterial (Sterile) verrucous endocarditis.
1-3 cm warty deposits on any heart valve, distinctively on either surface of the leaflets
vegetations in infective endocarditis are larger
vegetations in rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets
rheumatic heart disease == molecular mimicry with streptococcal antigens
Cns sle
noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted
may be due to endothelial damage by autoantibodies or immune complexes
Spleen sle
Splenomegaly, capsular thickening, and follicular hyperplasia.
onion skin lesions: central penicillinary arteries may show concentric intimal and smooth muscle cell hyperplasia
Lungs sle
Pleuritic and pleural effusions happen to about half of patients.
Chronic interstitial fibrosis and secondary pulmonary HTN
Clinical SLE
Typically presents in young women.
Course of the disease is variable and unpredictable.
Presentation can be overt or subtle.
butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints, pleuritic chest pain, and photosensitivity
Generic anti-nuclear antibodies (ANAs) found in almost every case, but these are not specific
Can have renal involvement.
Hematuria, red cell casts, proteinuria, and sometimes present as classic nephrotic syndrome.
Increased number of infections due to immune system dysfunction or treatment with immunosuppressive drugs.
disease flares are treated with corticosteroids or other immunosuppressive drugs.
most common causes of death are typically from renal failure, infections, and CAD.
Choriod discoid lupus erythematous DLE
disease in which skin looks like SLE but there are no other systemic manifestations
Skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border
localized, deep, and scarring – opposite of CLE
Can present on any skin, but most commonly on the face and scalp.
DLE is characterized by a rash similar to SLE, but with immune complex deposition only in sun-exposed areas of the skin, a positive ANA test result in a few cases, absence of anti-Sm or anti-dsDNA antibodies, and absence of serious renal disease
positive for generic ANAs but antibodies to dsDNA are rarely present
deposition of immunoglobulin and C3 at the dermoepidermal junction similar to SLE
Subacute cutaneous lupus erythematous
Presents with predominant skin involvement but distinguished from chronic discoid lupus erythematosus
skin rash is typically widespread, superficial, and non-scarring
Most patients have mild systemic symptoms consistent with SLE
strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype
intermediate between SLE and lupus erythematosus localized to the skin
Drug induced lupus erythematous
Lupus Erythematous-like syndrome can develop in patients taking a variety of drugs like hydralazine, procainamide, isoniazid, and D-penicillamine
many of these drugs are associated with the development of ANAs, but most patients are asymptomatic
Can also come from treatments of anti-TNF therapy which is used to treat diseases like RA and other autoimmune diseases.
Affects multiple organs, but renal and CNS involvement is uncommon.
disease goes away once the drug is removed
anti-histone antibodies
Sjorgen syndrome
Characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands by lymphocytes that eventually leads to inflammation –> tissue damage –> fibrosis
Sicca syndrome
me when it occurs as a primary disease. more often comorbid with another autoimmune disease (secondary form
Target of Sjorgen
lacrimal and salivary glands are the main target; respiratory and gastrointestinal tracts, and vagina == also affected
Histo Sjorgen
periductal and perivascular lymphocyte infiltration of major and minor salivary ducts
patients at high risk for developing B-cell lymphoma
Mikulzicz syndrome
C ombination of lacrimal and salivary gland inflammation and enlargement from any cause
Etiology and pathogenesis Sjorgen
antibodies against ribonucleotide proteins SS-A (Ro) and SS-B (La) are present in as many as 90% of patients
sensitive but not specific
serologic markers for Sjogren Syndrome
pathogenesis: aberrant T cell and B cell activation are both implicated
initiating trigger may be a viral infection of the salivary glands –> local cell death –> release of tissue self-antigens
in susceptible individuals, self-reactive lymphocytes to these antigens may have escaped tolerance
Clincial Sjorgen
Typically seen in women aged 50-60.
Symptoms results from destruction of exocrine glands
Keratoconjunctivitis: blurring of vision, burning, and itching; thick secretion accumulate in the conjunctival sac
Xerostomia: difficultly in swallowing solid foods, decrease in taste, cracks and fissures in the mouth, dryness of the buccal mucosa.
Can also have:
Parotid gland enlargement.
Dryness of the nasal mucosa –> epistaxis, perforated septum
Recurrent bronchitis and pneumonitis.
Extraglandular Disease in 33% of patients – more common with high anti-SS-a titers
Synovitis.
Diffuse pulmonary fibrosis.
Peripheral neuropathy.
defects of tubular function (i.e. renal tubular acidosis, uricosuria, and phosphaturia) often seen and associated with tublointestinal nephritis
glomerular lesions are rare (different than SLE
Pathology sjorgen
Biopsy of the lip to examine the minor salivary glands is essential for the diagnosis of Sjogren syndrome.
lymph nodes are often hyperplastic
Intense lymphocytic response in the involved tissues
Early: mix of polyclonal B and T cells
Later: a dominant B cell clone emerges and creates a marginal zone lymphoma
Scleroderma/systemic sclerosis
racterized by:
Chronic inflammation thought to be the result of autoimmunity.
Widespread damage to small blood vessels.
Progressive interstitial and perivascular fibrosis in the skin (early) and multiple organs like the GI tract, kidneys, heart, muscles, and lungs later
deposition of dense collagen in the dermis with virtual absence of appendages (e.g. hair follicles
Prognosis scleroderma
Majority progress to death from renal failure, cardiac failure, pulmonary insufficiency, or malabsorption
Diffuse scleroderma
widespread skin involvement at onset, with rapid progression
Limited scleroderma
skin involvement is often confined to fingers, forearms, and face, with visceral involvement late.
previously described as CREST Syndrome
Calcinosis: calcium deposits form in the skin
Raynaud phenomenon: fingers turn white after exposure to temperature changes or emotional events
Esophageal dysmotility: dysphagia (trouble swallowing) due to abnormal esophageal contraction
Sclerodactyly: localized thickening and tightness of the skin of the fingers and toes; often leads to atrophy of the underlying soft tissues (pressure atrophy)
Telangiectasia: benign skin condition; widened venules cause threadlike red lines or patterns on the skin
Etiology scleroderma
Thought to be related to:
Autoimmunity
Vascular damage
Fibrosis
Clincial scleroderma
Female-to-male ratio of 3 : 1.
Peak incidence in the 50-60-year age group.
distinctive features are the striking cutaneous changes, especially skin thickening
Raynaud phenomenon.
Episodic vasoconstriction of the arteries and arterioles of the extremities
Seen in virtually all patients and precedes other symptoms in 70% of cases – sensitive, not specific
Dysphagia from esophageal fibrosis that leads to hypomotility.
lower two-thirds of the esophagus often develops a rubber-hose-like inflexibility
abdominal pain, ileus, or malabsorption syndrome with weight loss and anemia == intestinal involvement
Respiratory difficulty attributable to pulmonary fibrosis
as treatment of the renal crises has improved, pulmonary disease has become the major cause of death
Myocardial fibrosis leading to arrhythmias or cardiac failure.
Renal:
Mild proteinuria (rarely severe enough to cause nephrotic syndrome)
Malignant hypertension –> fatal renal failure
virtually all patients have ANAs that react with a variety of nuclear antigens
anti-Scl 70 == highly specific; more likely to have pulmonary fibrosis and peripheral vascular disease
anticentromere == associated with CREST syndrome
What i scleroderma ? What leads to fibrosis? What are three hallmarks
progressive fibrosis involving the skin, GIT, and other tissues
What leads to the fibrosis in scleroderma?
fibrosis may be the result of activation of fibroblasts by cytokines produced by T-cells and alternatively activated macrophages
What are the three hallmarks of scleroderma?
chronic inflammation, widespread damage to small blood vessels, progressive interstitial and perivascular fibrosismixed CT disease-anti U1 ribonucleotide
Mixed CT disease -anti U1 ribonucleotide
A disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis.
serologically: high titers of antibodies to ribonucleotide particle-containing U1 ribonucleotide protein
synovitis of the fingers
Raynaud phenomenon
mild myositis – may be accompanied by a rash (dermatomyositis)
renal involvement is mild
good response to corticosteroids (at least in short term)
Suggested that “mixed connective tissue disease” is not a distinct entity, rather different patients represent subsets of SLE, systemic sclerosis, and polymyositis.
Disease can (but not always), evolve into classic SLE or systemic sclerosis (scleroderma).
Serious complications:
Pulmonary hypertension, interstitial lung disease, and renal disease.IgG4 related disease
IgG4 related disease
Most often affects middle-aged and older men.
1st characterized in autoimmune pancreatitis.
Now reported in virtually all organs.
Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal fibrosis, and inflammatory pseudotumors of the orbit, lungs, and kidneys.
Characterized by:
Tissues infiltrated dominated by IgG4 antibody-producing plasma cells and lymphocytes (mainly T cells).
Storiform fibrosis.
Obliterative phlebitis.
Usually increased serum IgG4.
Pathogenesis unknown and unclear if it’s really autoimmune
Recognition of alloantigens in Ryan grafts
Direct path and indirect
Direct pathway
Uses the APCs from the donor. Dendritic cells in the donor organs are the most important APCs for initiating the antigraft response MHC class I presents the antigen to the CD8 cells. The CD8 cells then proliferate to attack the blood vessels in the organ to cause endothelitis or to attack things like ducts or renal tubules. MHC class II molecules presents the antigen to CD4 cells which then make IFN-γ to activate macrophages. The macrophages can then go and attack things like ducts or renal tubules. the allogeneic MHC molecules with bound peptide resemble or mimic the self MHC-foreign peptide complexes that are recognized by self MHC-restricted T cells. recognition of allogeneic MHC molecules is a cross-reaction of T cells selected to recognize self MHC plus foreign peptides Figure 6-32 donor class I and class II MHC antigens on APCs in the graft (along with costimulators) are recognized by host CD8+ T cells and CD4+ Helper T Cells CD4+ Helper T Cells proliferate and produce cytokines (IFN-γ) --> tissue damage by a local inflammatory reaction CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells
Indirect pathway
The recipient’s APC presents the antigen to the CD4 cell which can then activate macrophages or B cells which then make plasma cells to attack the blood vessels.
The recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the recipient’s own APCs
The indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g. microbial) antigens. The indirect pathway generates CD4+ T Cells that enter the graft and recognize graft antigens being displayed by host APCs that have also entered the graft.
This is a Type IV (Delayed) Hypersensitivity
CD8+ CTLs generated by the indirect pathway cannot kill graft cells because these CTLs recognize graft antigens presented by the host’s APCs and cannot recognize the graft cells directly.
principal mechanism of cellular rejection may be T-cell mediated cytokine production and inflammation
Figure 6-32
graft antigens are picked up, processed, and displayed by host APCs and activate CD4+ T Cells
CD4+ T Cells damage the graft by an inflammatory reaction and stimulate B lymphocytes to produce antibodies
Acute cellular rejection
Most commonly seen within the initial months after transplantation or if the patient stops taking their immunosuppressive regimen.
Clinical and biochemical signs of organ failure.
Cytokines secreted by activated CD4+ T cells.
Inflammation results in increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages) –> graft injury is caused by activated macrophages
endothelitis with intimal injury occurs, but this can be treated with corticosteroids
Ex.: Renal Transplant Acute Cellular Rejection
CD3+ T-cells infiltrate the tissue and damage (tubular) epithelium by direct cytotoxicity and by release of cytokines (i.e. IFN-γ –> macrophages
Chronic rejection
Lymphocytes react against alloantigens in the vessel wall and secrete cytokines that induce local inflammation.
may stimulate the proliferation of vascular endothelial and smooth muscle cells.
Can be insidious or can be from many acute rejections that build up over time.
ischemic changes with vascular narrowing, interstitial and glomerular fibrosis and blood vessel thickening occur in chronic rejection, which is generally not reversible.
“intimal thickening with luminal narrowing
Antibody mediated reactions
Hyperacute
Occurs when preformed antidonor antibodies are present in the circulation of the recipient.
Can develop in persons with: previous transplant, prior blood transfusions, and multiparous women.
Cross-matching now makes this very rare.
fibrinoid necrosis and thrombosis are typical of hyperacute rejection
Antibody mediated reactions, acute antibody mediated rejection
Antidonor antibodies produced after transplantation
Initial target of these antibodies seems to be the graft vasculature
Chronic antibody mediated rejection
Usually develops insidiously.
Primarily affects vascular components.
antibodies are detected in the circulation but are not readily identified within the graft
Methods of increasing graft survival
HLA matching:
In kidney transplants: substantial benefit if all the polymorphic HLA alleles are matched (both inherited alleles of HLA-A, -B, and DR).
Not done for transplants of liver, heart, and lungs – other factors override the potential benefits of HLA matching
Immunosuppressive therapy (necessary but increased risk of infections)
Steroids (which reduce inflammation).
Mycophenolate mofetil (which inhibits lymphocyte proliferation).
Tacrolimus (FK506) - inhibits T cell functions.
predecessor: cyclosporine
MOA: Tacrolimus –| calcineurin (phosphatase) –> NFAT –> IL-2 (T-cell growth factor)
T cell- and B cell-depleting antibodies
Pooled intravenous IgG (IVIG): suppresses inflammation by unknown mechanisms.
Plasmapheresis: used in cases of severe antibody-mediated rejection.
The plasma is taken out of the body, it is spun down and the layer containing the antibodies is removed and the rest of the plasma is placed back into the body
Polyomavirus virus
establishes latent infection in the epithelial cells of the lower genitourinary tract
Can reactivate, infect renal tubules and may even cause graft failure
Increased risk for developing immunosuppression and infections (from rectivation of latent viruses)
EBV-induced lymphomas. Human papillomavirus (HPV)-induced squamous cell carcinomas. Kaposi sarcoma (HHV8
Transplantation hematopoietic stem cell
Used for:
Hematologic malignancies.
Bone marrow failure syndromes (such as aplastic anemia).
Inherited stem cell defects (such as sickle cell anemia, thalassemia, and immunodeficiency states).
Usually harvested from peripheral blood after they are mobilized from the bone marrow by administration of hematopoietic growth factors.
Can also be obtained from umbilical cord blood of newborn infants.
Most of the time, the recipient is irradiated or treated with high doses of chemotherapy to destroy the immune system then allowing the transplanted stem cells to engraft.
Two problems that are unique to HSC transplantation are GVHD and immunodeficiency
GVHD
Occurs when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients.
engrafted marrow is not completely matched for MHC loci and thus contains immunocompetent donor cells that can proliferate, recognize host cells as foreign, and mount an immune response against host tissue
The skin, liver, and GIT epithelium are typically effected – systemic effects
The transferred cells recognize alloantigens in the host and attack host tissues.
immunocompetent T-cells present in the donor inoculum recognize the recipients HLA antigens as foreign and react accordingly
Seen most commonly in the setting of HSC transplantation.
Rarely occurs following transplantation of solid organs rich in lymphoid cells (e.g., the liver) or transfusion of unirradiated blood.
To minimize GVHD, HLA-matching with precise DNA sequencing-based methods for molecular typing is critical
Acute GVHD
Within days to weeks after allogeneic bone marrow transplantation.
Any organ may be affected, but the majority of clinical manifestations from:
Immune system, skin, liver, and intestines
Chronic GVHD
May follow the acute syndrome or may occur insidiously.
Extensive cutaneous injury, with destruction of skin appendages and fibrosis of the dermis
Chronic liver disease manifested by cholestatic jaundice is also frequent – UTAH QUESTION
hyperbilirubinemia
Damage to the gastrointestinal tract may cause esophageal strictures.
The immune system is devastated, with involution of the thymus and depletion of lymphocytes in the lymph nodes.
Recurrent and life-threatening infections.
Some patients develop manifestations of autoimmunity
GVHD
Mediated by T lymphocytes contained in the transplanted donor cells.
So depletion of donor T cells before transfusion virtually eliminates the disease.
Unfortunately leads to:
Recurrence of tumor in leukemic patients.
Deliberate induction of graft-versus-leukemia effect by infusion of allogeneic T cells used to treat chronic myelogenous leukemia that has relapse after HSC transplantation
Increased incidence of graft failures.
Increased rates of EBV-related B-cell lymphoma
Wha causes immunodeficiency after bone marrow transplant
Can be from:
Prior treatment.
Myeloablative preparation for the graft.
Delay in repopulation of the recipient’s immune system.
Attack on the host’s immune cells by grafted lymphocytes.
Profoundly immunosuppressed
Any infection.
Re-activation of cytomegalovirus (CMV) especially bad –> CMV-induced pneumonitis can be fatal
How do How do host T-cells recognized foreign HLA antigens of the graft in the direct and indirect pathways
DIRECT: host T-cells recognize foreign HLA antigens of the graft on APCs in the graft
INDIRECT: host T-cells recognize foreign HLA antigens of the graft after uptake and presentation by host APCs
What is the morphology of rejection mediated by preformed antibodies
Hyperacute rejection == thrombosis, ischemic damage, and rapid graft failure
How does acute cellular rejection damage tissue
T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions
What do the antibodies in acute humoral rejection target
Graft vasculature
What do the antibodies in acute humoral rejection target
Graft vasculature
What is sign hallmark chronic rejection
arteriosclerosis
activated T-cells secrete cytokines that induce proliferation of vascular smooth muscle cells
antibodies cause endothelial injury
vascular lesions + T-cell reactions cause parenchymal fibrosis
intimal thickening and luminal narrowing
Scid
Defects in both humoral and cell-mediated immune responses.
lack of T cells means you can’t activate B cells
Infants present with:
Prominent thrush (oral candidiasis).
Extensive diaper rash.
Failure to thrive.
Some infants develop GVHD (manifested by morbiliform rash).
Maternal T cells are transferred across the placenta and attack the fetus.
Extremely susceptible to recurrent, severe infections:
Candida albicans, Pneumocystis jiroveci, Pseudomonas, CMV, varicella, and a whole host of bacteria.
Without HSC (BMT) transplantation, death occurs within the first year of life.
Gene therapy may also be possible.
X-linked most common, but can also be autosomal recessive disorders.
50% of SCID cases are caused by an X-linked mutation in the common γ chain for cytokine receptors
50% of SCID cases are caused by autosomal recessive mutations in the gene encoding adenosine deaminase (ADA)
X linked agammaglobulinemia /bruton agammaglobulinamia
Failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells.
B cells are absent or markedly decreased in the circulation.
CD19+ pre-B cells are found in normal numbers in bone marrow – do not express BCR (Ig)
Serum levels of all classes of immunoglobulins are depressed.
Plasma cells are absent throughout the body.
germinal centers of MALT and GALT are underdeveloped
caused by mutations in a cytoplasmic tyrosine kinase called Bruton tyrosine kinase (Btk)
Btk is associated with the Ig receptor complex of pre-B and mature B cells and is needed to transduce signals from the receptor. When mutated, the pre-B cell receptor cannot deliver signals and maturation stops at this stage..
T cell–mediated reactions are normal.
able to handle most (but not all) viral, fungal, and protozoal infections
Usually becomes apparent after ~6 months of age once maternal immunoglobulins are depleted.
Recurrent Infections (ones that rely on antibodies to clear them):
Bacterial infections of the respiratory tract.
acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia
Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus
normally opsonized by antibodies and cleared by phagocytes – not in the case of agammaglobulinemia
Viruses in the bloodstream or mucosal secretions.
antibodies are important for neutralizing infectious viruses
Enteroviruses, such as echovirus, poliovirus, and coxsackievirus.
infect the GIT and disseminate to the nervous system via blood
Giardia lamblia (intestinal protozoan)
normally resisted by secreted IgA, causes persistent infections in persons with x-linked agammaglobulinemia
~35% develop autoimmune diseases (like arthritis and dermatomyositis).
Likely from the breakdown of self-tolerance.
Chronic infections may also play a role.
Treatment:
Replacement therapy with immunoglobulins (IVIG
Digeorge
DiGeorge Syndrome (Thymic Hypoplasia)
T-cell deficiency.
Results from failure of development of the third and fourth pharyngeal pouches.
Gives rise to:
Thymus
Loss of T cell-mediated immunity.
Ig levels may be normal or reduced depending on the severity of the T-cell deficiency
Poor defense against certain fungal and viral infections.
Parathyroids
Hypocalcemia, which can lead to tetany.
Some of the C cells of the thyroid.
Ultimobranchial body.
Congenital defects of the heart and great vessels.
May also have abnormal appearance of the mouth, ears, and facies.
Considered a component of the 22q11 deletion syndrome
Hyper IgM syndrome
Patients make IgM antibodies but cannot produce IgG, IgA, and IgE antibodies
From defect in ability of helper T cells to deliver activating signals to B cells and macrophages
CD40/CD40L interaction triggers Ig class switching and affinity maturation in B cells, and stimulates the microbicidal functions of macrophages
CD40 on B cells, macrophages, and dendritic cells
CD40L on CD4+ Helper T cells
X-linked (70%) or autosomal recessive
Patients present with recurrent pyogenic infections
level of opsonizing IgG antibodies is low
Those with CD40L mutations also susceptible to Pneumocystis jiroveci pneumonia – intracellular organism
CD40L mediated macrophage activation is a key reaction of cell mediated immunity that eliminates pneumocystis jiroveci
Occasionally, IgM antibodies react with blood cells and lead to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. RBCs are already prone to hemolysis by complement
Common variable immunodefieny
Group of disorders with hypogammaglobulinemia (low Ig)
Usually all antibody classes; sometimes only IgG
Diagnosis requires exclusion of other diseases of decreased antibody production
Sporadic and inherited forms
Have normal/near-normal numbers of B cells (as opposed to X-linked agammaglobulinemia)
But they aren’t able to differentiate into plasma cells
Clinically resembles X-linked agammaglobulinemia – manifestations are caused by antibody deficiency
Although M=F; onset of symptoms childhood or adolescence (as opposed to X-linked agammaglobulinemia
Isolated iga defiency
Fairly common: ~1 in 600 of European descent
Extremely low levels of both serum and secretory IgA
Familial or acquired in association with toxoplasmosis, measles, or some other viral infection
Most asymptomatic
Symptomatic patients present with recurrent sinopulmonary infections and diarrhea
IgA is the major antibody in external secretions, therefore, mucosal defenses are weakened and infections occur in the respiratory, gastrointestinal, and urogenital tracts.
some patients also deficient in IgG2 and IgG4 – particularly prone to infection
patients have a high frequency of respiratory tract allergy and autoimmune diseases (especially SLE and rheumatoid arthritis).
patients transfused with IgA-containing blood can develop severe/fatal, anaphylactic reactions, because the IgA behaves like a foreign antigen
Wiskott-Aldrich syndrome
X-linked – WASP gene
WASP protein believed to anchor membrane receptors to cytoskeleton components
Thrombocytopenia, eczema, and recurrent infection that leads to early death.
Thymus is morphologically normal but there is progressive loss of T lymphocytes in the peripheral blood and T cell zones (paracortical areas) of lymph nodes
patients do not make antibodies to polysaccharide antigens
patient response to protein antigens is poor
IgM levels in serum are low; IgG levels in serum are normal; IgA and IgE are elevated
patients prone to developing B-cell lymphomas
Treatment: hematopoietic stem cell transplantation
this is the only treatment
Ataxia telangiectasia
Autosomal-recessive; chromosome 11, ataxia telangiectasia mutated (ATM) protein
ATM is a sensor of double strand breaks in DNA; phosphorylates (activates) p53
ATM contributes to the stability of DNA double-strand break complexes during V(D)J recombination
Abnormal gait (ataxia), vascular malformations (telangiectasia), neurologic deficits, increased incidence of tumors, and immunodeficiency.
may affect both B and T cells
defective production of isotype switched antibodies, mainly IgA and IgG2
upper and lower respiratory tract infections, multiple autoimmune phenomenon, and increasingly frequent cancers with advancing age
Secondary (acquired) immunodeficiency
Cancer, diabetes and other metabolic diseases
Complications of cancers
Infections
Acquired immunodeficiency syndrome (AIDS)
Malnutrition
Immunosuppressive therapy
Irradiation
Chemotherapy for cancer and other diseases
Acquired immunodefiency syndrome
Caused by the human immunodeficiency virus (HIV) a retrovirus.
Characterized by profound immunosuppression.
Opportunistic infections, secondary neoplasms, and neurologic manifestations.
By end of 2009 in US: > 1 million cases of AIDS had been reported.
Ages 25-44
2nd leading cause of death in men and the 3rd for women.
Global heavy burden in Africa and Asia.
Rates of new infections is decreasing
Properties HIV
HIV == non-transforming retrovirus of the lentivirus family
Two forms (similar):
HIV-1 most common in the US, Europe, and Central Africa.
HIV-2 principally in West Africa and India.
Virus core contains
Major capsid protein p24.
Most abundant viral antigen.
ELISA test used to diagnose HIV infection.
Two copies of viral genomic RNA.
Three viral enzymes (protease, reverse transcriptase, and integrase).
Core is surrounded by a matrix protein called p17.
gp120 and gp41 stud the viral envelope (critical for HIV infection of cells).
HIV infection
HIV first infects T cells, dendritic cells, and macrophages (all have CD4).
Establishes itself in lymphoid tissues.
It can remain latent for long periods.
Active viral replication → more infection of cells → progression to AIDS
MOA HIV infection
The gp120 binds to the CD4 on a target cell which leads to conformational change that forms a new recognition site on gp120 for CCR5 and CDCR4 co-receptors
chemokines sterically hinder HIV infection of cells in culture by occupying their receptors, and therefore, the level of chemokines in the tissues may influence the efficiency of viral infection in vivo
The gp41 is then able to penetrate the target membrane and allow the HIV virus to fuse with the membrane and insert its RNA.
The HIV RNA then uses reverse transcriptase to make a pro-viral DNA copy and insert into the target’s DNA.
Then more HIV are made using the target’s machinery and the baby HIV bud off
HIV chemokine receptors
HIV isolates can be distinguished by the receptor it uses:
R5 strains use CCR5
Preferentially infects cells of the monocyte/macrophage lineage (M- tropic).
90% of cases, this strain dominates in acutely infected.
~1% of white Americans (rarely Africans or East Asians) are homozygous for defective copies of the CCR5 gene.
Resistant to infection and the development of AIDS associated with R5 HIV isolates.
~20% of individuals are heterozygous.
Onset of disease after infection is delayed.
acute (early) infection is characterized by infection of memory CD4+ T-cells (which expressed CCR5) in mucosal lymphoid tissues, and death of many infected cells
X4 strains use Cxcr4
Preferentially infect T cells (T-tropic).
Even infect thymic T-cell precursors which leads to greater T-cell depletion and impairment.
This strain gradually accumulates over time – especially virulent because T-tropic viruses are capable of infecting many T-cells and even thymic T-cell precursors to cause greater T-cell depletion and impairment.
R5X4 is dual-tropic and uses both
R5X4
Dual tropic and uses both
HIV infection
Infects memory and activated T cells.
Hard time infecting naive T cells.
Contain an active form of an enzyme that leads to mutations in the HIV genome.
APOBEC3G (for apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G).
cytidine deaminase that introduces cytosine-to-uracil mutations in the viral DNA that is produced by reverse transcriptase
this inhibits further DNA replication by mechanisms that are unknown
Activation of T-cells converts cellular APOBEC3G into an inactive, high molecular mass complex
virus can replicate in previously activated T-cells but not naïve T-cells
HIV has evolved to counteract this:
Viral protein Vif binds to APOBEC3G which leads to degradation by cellular proteases
HIV infection
Thrives when the host T cells and macrophages are activated by antigenic stimulation.
By HIV itself.
By other infecting microorganisms (like other STDs).
Completion of the viral life cycle in latently infected cells occurs only after cell activation.
Stimulation of cells:
Ultimately leads to release of NF-κB → goes to the nucleus → increased IL-2 and IL-2R transcription, increased HIV DNA transcription
can happen by environmental antigen (e.g. pollen or microbe) – this is a physiologic response
T cell depletion
Mainly by direct cytopathic effects of the replicating virus.
~100 billion new viral particles are produced every day → 1-2 billion CD4+ T cells die each day.
For a while, the immune system can replace the dying T cells.
But eventually, it can’t keep up.
Other mechanisms also contribute to T cell death.
activation induced cell death: chonic activation of uninfected cells exhausts them –> apoptosis
non cytopathic (abortive) HIV infection activates the inflammasome pathway –> pyroptosis
inflammatory cytokines and cellular components are released –> recruits more cells and increases the number of cells that can be infect
important role in spread of the infection
HIV macrophages
HIV-1 can infect and multiply in terminally differentiated non-dividing macrophages.
Dependent on the viral Vpr gene
macrophages allow viral replication but are resistant to the cytopathic effects of HIV.
May be reservoirs of infection whose output remains largely protect from host defenses
May act as portals of infection.
90% of acute HIV infection is predominantly M- tropic strains
Dendritic cells hiv
Mucosal dendritic cells
are infected by the virus and transport the virus to regional lymph nodes
Then transmitted to CD4+ T cells
DCs express a lectin-like receptor that specifically binds HIV and displays it in an intact, infectious form to T cells
Follicular dendritic cells (in the germinal centers of lymph nodes)
Potential reservoirs of HIV
Most virus particles are found on the surface of their dendritic processes
Follicular DCs have receptors for the Fc portion of immunoglobulins –> trap HIV virions coated with anti-HIV antibodies
trapped HIV virions retain the ability to infect CD4
B cell hiv
Polyclonal activation of B cells.
Characteristics
Germinal center B-cell hyperplasia (particularly early in the disease course)
Bone marrow plasmacytosis (high number of plasma cells in the bone marrow)
Hypergammaglobulinemia
Formation of circulating immune complexes – Type III Hypersensitivity
CMV, EBV, and gp41 are polyclonal B-cell activators
HIV infected macrophages –> IL-6 –> B-cell proliferation
most common neoplasms seen in association with AIDS are B cell non-Hodgkin lymphomas
Patients with AIDS can’t mount antibody responses to newly encountered antigens.
Not just because of loss of T cell help.
impaired humoral immunity renders these patients prey to disseminated infections caused by encapsulated bacteria (e.g. staphylococcus pneumoniae and haemophilus influenzae) which require antibodies for effective opsonization and clearance
HIV and brain
Nervous system is a major target of HIV infection.
40-60% have clinically apparent neurologic dysfunction.
Infects macrophages and microglial cells. It is believed that HIV is carried into the brain by infected monocytes.
Mechanism of HIV-induced damage of the brain is poorly understood
Acute retroviral syndrmoe
– the “flu-like symptoms”
Clinical presentation of the initial spread of the virus and the host response.
Seen in 40-90% of individuals who acquire the virus.
Typically occurs 3-6 weeks after infection.
Resolves spontaneously after 2-4 weeks.
Symptoms:
Sore throat, myalgias, fever, weight loss, and fatigue.
Rash, cervical adenopathy, diarrhea, and vomiting
Viral load HIV
Extent of viremia (measures HIV-1 RNA levels in the blood).
viral load at the end of the acute phase reflects the equilibrium reached between the virus and the host response
level of steady-state viremia (viral set point) can predict rate of decline of CD4+ T cells (i.e. progression of HIV)
for clinical management, blood CD4+ T-cell counts are perhaps the most reliable short-term indicator of disease progression. For this reason, CD4+ cell counts and not viral load are the primary clinical measurements used to determine when to start antiretroviral therapy
Clinical latency period hiv
Lymph nodes and the spleen are sites of continuous HIV replication and cell destruction
Number of circulating blood CD4+ T cells steadily declines.
Few or no clinical manifestations.
Oral candidiasis (thrush), vaginal candidiasis, herpes zoster, and maybe mycobacterial tuberculosis.
Autoimmune thrombocytopenia
HIV evades immune detection
Destroys the CD4+ T cells that are critical for effective immunity.
Antigenic variation.
Down-modulation of class I MHC molecules on infected cells.
Viral antigens are not recognized by CD8+ CTLs.
May also evolve and switch from relying solely on CCR5 to enter its target cells to relying on either CXCR4 or both CCR5 and CXCR4.
Associated with more rapid decline in CD4+ T-cell counts
Progression to axis
Typically about 7-10 years.
Rapid progressors: 2-3 years.
Long-term non-progressors (5-15%).
Asymptomatic, stable CD4+ T cell counts, and low viremia for 10 or more years.
Elite controllers (~1%)
Undetectable plasma virus (<50-75 RNA copies/mL).
Clinical features AIDS
Fever and weight loss Diarrhea Generalized lymphadenopathy Neurologic disease Multiple opportunistic infections Secondary neoplasms
AIDS defining opportunistic infection
Protozoal and helminthic infections
Cryptosporidiosis or isosporidiosis (enteritis)
Pneumocytosis (pneumonia or disseminated infection)
Toxoplasmosis (pneumonia or CNS infection)
Fungal infections
Pneumocystis jiroveci
Candidiasis (esophageal, tracheal, or pulmonary)
Cryptococcosis (CNS infection)
Coccidioidomycosis (disseminated)
Histoplasmosis (disseminated)
Bacterial infections
Mycobacteriosis
Nocardiosis
Salmonella infections
Viral infections
Cytomegalovirus
Herpes simplex virus
Varicella-zoster virus
Progressive multifocal leukoencephalopathy via the JC virus
Neoplasma aids
Kaposi sarcoma via the HHV8 virus (herpesvirus, KSHV)
Characterized by the proliferation of spindle-shaped cells that express markers of both endothelial cells (vascular or lymphatic) and smooth muscle cells. There is a profusion of slit-like vascular spaces, suggesting that the lesions arise from primitive mesenchymal precursors of vascular channels.
KS lesions display chronic inflammatory cell infiltrates (macrophages and lymphocytes)
Primary lymphoma
unchecked proliferation of B cells infected with oncogenic herpesviruses (i.e. EBV, HHV8/KSHV) in the setting of profound T cell depletion
germinal center B-cell hyperplasia in the setting of early HIV infection
majority of lymphomas seen in AIDS patients are not associated with EBV or KSHV
germinal center B-cell hyperplasia increases the number of B-cells that are “at risk” for acquiring potential lymphoma initiating events
Burkitt lymphoma and diffuse large B-cell lymphoma are associate with MYC and BLC6 mutations
Invasive cancer of uterine cervix or anus via HPV
most common neoplasms seen in association with AIDS are B cell non-Hodgkin lymphomas
HAART
Combination of 3-4 drugs that block different steps of the HIV life cycle.
Dramatically alters the course of HIV infection and incidence of opportunistic infections and tumors.
E.g. P. jiroveci and Kaposi sarcoma.
Can suppress virus levels below the level of detection.
Stops the loss of CD4+ T cells.
Over time, peripheral CD4+ T-cell count slowly increase (often to normal).
Reduced transmission of the virus.
Especially from infected mothers to newborns.
Concern that with more people living with HIV increased risk of spreading the infection if vigilance is relaxed.
Downside of HAART
Immune reconstitution inflammatory syndrome
Some patients with advanced disease.
Antiretroviral therapy triggers a paradoxical clinical deterioration.
Occurs despite increasing CD4+ T-cell counts and decreasing viral load.
Not understood why this occurs.
Adverse side-effects of the drugs
Lipoatrophy (loss of facial fat)
Lipoaccumulation (excess fat deposition centrally)
Elevated lipids
Insulin resistance
Peripheral neuropathy
Premature cardiovascular kidney and liver disease
What protein on the HIV virus binds to CD4?
gp120
What protein on the HIV virus mediates fusion with the cell?
gp41
What are the main cellular targets of the HIV virus?
CD4+Helper T Cells, macrophages, and dendritic cells
What are the clinical manifestations of AIDS?
opportunistic infections, Kaposi sarcoma, B-cell lymphomas, and CNS abnormalities
Ok
Amyloidosis
Extracellular deposits of fibrillar proteins that leads to tissue damage and functional compromise
Abnormal fibrils are produced by the aggregation of misfolded proteins.
Fibrillar deposits bind a wide variety of proteoglycans and glycosaminoglycans (i.e. heparan and dermatan sulfate)
Associated with a number of inherited and inflammatory disorders.
progressive accumulation –> encroaches on and produces pressure atrophy of adjacent cells
Diagnosis usually made with tissue biopsy
Classification of amyloidosis
Immunocyte dyscrasias with amyloidosis (primary amyloidosis).
Associated Disease: multiple myeloma and other monoclonal plasma cell proliferations.
Major fibril protein: AL
amyloid light chain protein is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both
Chemically related precursor protein: Ig light chains (mostly λ)
Reactive systemic amyloidosis (secondary amyloidosis).
Associated Disease: chronic inflammatory conditions.
Major fibril protein: AA.
amyloid associated type of amyloid fibril protein is derived from a unique non-Ig protein made by the liver
Chemically related precursor protein: SAA (serum amyloid associated, acute phase protein)
In chronic inflammatory conditions (i.e. rheumatoid arthritis), the serum-associated amyloid precursor protein forms the major amyloid fibril protein AA. SAA is an acute phase reactant that increases with inflammatory conditions. CRP is also an acute phase reactant whose level is increased in inflammatory conditions, but unlike SAA, CRP does not form amyloid
Hemodialysis-associated amyloidosis. Associated Disease: chronic renal failure patients on long term hemodialysis for renal failure can develop amyloidosis as a result of deposition of β2-microglobulin Major fibril protein: Aβ2m Chemically related precursor protein: β2-microglobulin (part of MHC class I) Cardiac and heredofamilial forms of amyloidosis have fibrils derived from prealbumin transthyretin (TTR) senile cardiac amyloidosis resulting from deposition of transthyretin characterized by worsening congestive heart failure and pulmonary and peripheral edema; cardiomegaly Congo red-positive interstitial deposits of amorphous
Pathogenesis amyloidosis
amyloid is deposited in interstitial locations
Plasma Cell Disorders associated with amyloid are usually systemic in nature and of the AL type
malignant plasma cells synthesize abnormal amounts of a single Ig (monoclonal gammopathy) –> M protein spike on PAGE
malignant plasma cells often secrete free, unpaired κ or λ light chains == Bence-Jones protein
Bence-Jones proteins are excreted and concentrated in the urine
free light chains are present in the serum and urine, and also deposited in the tissues as amyloid
Heredofamilial amyloidosos (familial Mediterranean fever)
autoinflammatory syndrome associated with excessive production of the cytokine IL-1 in response to inflammatory stimuli
characterized clinically by attacks of fever accompanied by inflammation of serosal surfaces (i.e. peritoneum, pleura, and synovial membrane)
defective gene == pyrin
sometimes associated with widespread amyloidosis (AA type
Organs amyloidosos
Amyloidosis secondary to chronic inflammatory disorders:
Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid.
Other tissues as well.
Amyloidosis associated with plasma cell proliferations:
More often involves the heart, gastrointestinal tract, respiratory tract, peripheral nerves, skin, and tongue.
But not specific.
Localization of amyloid deposits in hereditary syndromes is varied
Congo red stain for amyloid
Best stain for diagnosis, the protein aggregates will turn red and then look apple green on fluorescence
Congo red stain under ordinary light imparts a pink or red color to tissue deposits
more striking and specific is the green birefringence of the stained amyloid when observed by polarizing microscopy
Clincial amyloidosis
Incidental finding with no clinical manifestations.
Cause serious clinical problems and even death.
Symptoms depend on the magnitude of the deposits and on the sites or organs affected.
Initial clinical manifestations are nonspecific.
Weakness, weight loss, light-headedness, or syncope
Prognosis. Amyloidosis
Poor
How is amyloidosis characterized
How is amyloidosis characterized?
amyloidosis is a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils
What are the three ways that proteins may deposit as amyloid?
excessive production of proteins that are prone to misfolding and aggregation
mutations that produce proteins that cannot fold properly and tend to aggregate
defective or incomplete proteolytic degradation of extracellular proteins
How do amyloid deposits damage tissue?
pressure atrophy
Do amyloids evoke an inflammatory response?
No
