FPP-Week 1 Flashcards
Plasma vs Serum
Plasma is fluid phase after centrifuge W HEPARIN
Serum is AFTER COAGULATION (removes clotting factors)
Complete Blood Count (CBC)
Erythrocyte/RBCs: 4.6-6.1 million/ul (mcl)
varies w/ altitude
Male: 4.6-6.1
Female: 4.2-5.4
Leukocyte/WBCs: 4-10 thousand/ul
Differential Count
Granulocytes: neutrophils: 34-71% eosinophils: 0-7 basophils: 0-1 Agranulocytes: monocytes: 5-12 lymphocytes: 19-53
Erythrocytes
RBCs 7.5um diameter no organelles or nucleus, biconcave Hb causes eosinophilia, makes 33% Also CA (carbonic anhydrase) -Band 3: binds ankyrin which binds spectrins which maintains biconcave shape (mutations cause spherocytosis) ABO and Rh Lifespan=120days hematocrit>55%: polycythemia (more RBCs) or erythrocytosis (bigger RBCs)
Neutrophils
polymorphonuclear, polys (PMN), lobulated nucleus
Anti-bacterial
granules: lysosomes and “specific” (don’t stain)
PMN to fit between cells (caspase)
1. release granules (degrade bacteria)
2. phagocytosis
3. respiratory burst (NADPH oxidase) superoxides
Lifespan=few days
Eosinophils
bi-lobed nucleus
anti-parasitic (also allergies)
large red (eosin) granules, crystalloid center
kills parasites via major basic protein (MBP)
phagocytize antigen-antibody complex
secrete leukotrienes, LTC4 (asthma), and PAF
lifespan=few weeks
If activated: Neoplasia, Asthma, Allergy, Connective tissue disease, Parasitic disease (NAACP)
Have CCR3 (Eotaxin and RANTES receptor)
Steroids cause apoptosis
Basophils
Nucleus obscured by blue granules heparin and histamine like mast cells 1. antigen invades system 2. plasma cell makes IgE 3. IgE binds basophil 4. Later on, antigen binds IgE on mast cell, causes granule release, allergic response lifespan=years
Monocytes
Largest WBC, indented/horseshoe nucleus
in tissues, become APCs or macrophages
Lymphocytes
B (bone marrow) and T (thymus)
T predominates in blood
cart-wheel nucleus
Megakaryocytes
Usually only in bone marrow
buds off platelets
Platelets
2um, 300,000/ul
granulomere - clotting factors and PDGF
hyalomere - microtubules (outside edge)
Hypertrophy
increase in size of cells
physiologic: functional demand or hormonal (skeletal muscle, uterus in pregnancy)
pathologic: cardiac muscle in hypertension
Hyperplasia
Increase in cell number
laile and stable cells
physiologic: hormonal in breast tissue and of liver post-resection, wound healing
pathologic: excessive growth factors (e.g. endometrial or prostatic), increased risk on cancer
BPH-no increased cancer risk, nodules
also skin warts from viral infxns (papilloma)
Atrophy
Decrease in cell size
physiologic: loss of hormone stimulation
pathologic: decreased functional demand, loss of innervation, malnutrition
Metaplasia
One cell type replaced by another
adaptive to chronic stress, reversible, risk of cancer
Epithelial: ciliated columnar->squamous (smokers), squamous->gastric (distal esophagus (Barrett) reflux)
Mesenchymal: bone formation in soft tissue at injury sites
Necrosis
enlarged cell karyolysis disrupted plasma membrane (blebs) Enzymatic digestion of cell contents (may leak) Causes adjacent inflammation Always pathologic increased eosinophilia
Apoptosis
reduced cell size nucleus fragmentation into nucleosome-size Intact plasma membrane (blebs) cell components released in apoptotic bodies NO inflammation Often physiologic, sometimes pathologic increased eosinophilia chromatin condensation Regulated by Bcl-2, Cyt-C, Caspase
Reversible cell injury
fatty change (lipid vacuoles) e.g fatty liver
cell swelling, blebs, distended ER
clumped chromatin, swollen mitochondria
Coagulative necrosis
hypoxic or anoxic injury due to ischemia
persistence of dead cell outlines, loss of cell details
occurs in all solid organs (not brain)
Liquefactive necrosis
complete digestion of dead cells
common with bacterial or fungal infxns
also brain infarcts
Caseous necrosis
characteristic of TB
resembles cheese, crumbly
fragmented cells with loss of cell outlines
usually surrounded by border of inflammation (granuloma)
Gangrenous necrosis
ischemic coagulative necrosis of extremity
wet: when bacteria also present
also used for severe necrosis of other organs
Fat necrosis
Typical in pancreas
chalky white (fatty acids with Ca)
also when trauma to fatty tissue
Fibrinoid necrosis
Deposition of immune complexes in vascular wall
bright pink, amorphous
vasculitis syndromes
Pathologic calcification
Dystrophic: damaged or dying tissues, normal serum levels, basophilic
Metastatic: hypercalcemia, normal tissue (e.g. renal failure, increased PTH), interstitial tissues
Chronic Granulomatous Disease (CGD)
Functional absence of respiratory burst in neutrophils and monocytes (impaired bacterial killing)
NADPH oxidase, usually X-linked, can be auto recessive
Onset by age 2, infxn with S epidermidis, S marcescens, aspergillus
Tx: TM-sulfa, itraconazole,, bone marrow transplant
Dx test: DHR test, flow for superoxide production
Lack of superoxide-> lack of eat me signal on dead cells-> disordered inflammation
Leukocyte Adhesion Deficiency-1 (LAD-1)
Autosomal recessive deficiency of many adhesion molecules, shared beta chain (CD18)
bc lack adhesion molecules, leukocytes can’t adhere to endothelium to reach infxns
recurrent pyogenic infxns, delayed umbilical detachment, leukocytosis, no pus, decreased wound healing, impaired phagocytosis, chemotaxis, etc
Tx: aggressive infxn tx, bone marrow if severe
Dx: flow cytometry for CD18
Toll-Like Receptor (TLR) signaling
Most: MyD88, IRAK-> NFkB, Erk, Jnk, p38-> inflammatory cytokines
TLR3-> TRIF->IRF-3, IFN-B
TLR4-> both pathways
MyD88/IRAK4 deficiency
Primary immunodeficiency in innate immunity
S pneumoniae, S aureus, P aeruginosa
early onset, high mortality, but if make it to 8yo, then good
TxL IVIG/Abx prophylaxis
TLR3/TRIF pathway deficiency
Early onset herpes virus encephalitis
incomplete penetrance
Late Complement Deficiency
C5-C9 (form membrane attack complex)
recurrent meningococcal disease (N meningitidis)
Early Complement Deficiency
C2 most common, autosomal recessive
Screening test: CH50 (if 0, then individual complement deficiency, if low but >0, then consumption of complement problem)
Severe Combined Immunodeficiency (SCID)
Profound defect in cellular and humoral immunity
early onset, lots of infxns, failure to thrive
100% mortality w/o bone marrow transplant
screening: CBC, lymphopenia
confirmatory: lymphocyte enumeration (Tcells=0)
Also newborn screening–
TREC (T cell receptor excision circles) are marker for normal naive T cells, low in SCID, qPCR
22q11.2 Deletion Syndrome (DiGeorge Syndrome)
Wide clinical spectrum, CATCH22 (cardiac defects, abnormal faces, Thymic hypoplasia, cleft palate, hypocalcemia)
recurrent infxns, autoimmunity, some require IVIG
low set ears
Dx: DNA microarray, FISH
confirm: qPCR for haploinsufficiency TBX1 (CHW)
X-Linked Agammaglobulinemia (XLA)
No antibodies (85% of cases are XLA)
Recurrent otitis, sinsusitis, pneumonia
brinchiectasis if not dx early
Screening: IgG, IgA, IgM
Defecit in Btk, which leads to lack of “live” signal in B-cell development
Don’t use serological assays for dx (bc no antibodies), use direct methods only
Common Variable Immunodeficiency (CVID)
Decrease in IgG and low IgA or IgM
onset >4yo
clinical course is variable
Bronchiectasis (widening of bronchi) and interstitial lung disease are common
-treat similar to cystic fibrosis
also cancer
Don’t use serological assays for dx (bc no antibodies), use direct methods only
Type I hypersensitivity
anaphylaxis, asthma, allergies
IgE antibody-> mast cells, histamine, tryptase
Allergies: allergen->APC->Th2->B-cell->IgE-»>allergen->mast cell->histamine, tryptase, [leukotrienes, IL-3,4,5, MIP-1a, RANTES, Eotaxin, PAF, TNF]
Real bad real quick, then again 4hrs later when more cells get recruited (cytokines->T-cells and eosinophils)
Type II hypersensitivity
Cell, matrix-bound antigens
autoimmune hemolytic anemia, erythroblastosis fetalis, Goodpasture syndrome
IgG/IgM-> binds to antigen on cell surface-> phagocytosis or lysis of target cell (macrophages, NK cells (Fc receptor))
Type III hypersensitivity
Soluble antigens
serum sickness, systemic lupus erythematosis, arthus rxn, rheumatoid arthritis, farmer’s lung
antigen-antibody complexes (IgG)-> activated complement-neutrophils->deposit (vessel walls) and release toxic stuff
Kidneys, vessels, joints, skin destruction
Type IV hypersensitivity
Cell-mediated
TB, contact dermatitis (poison ivy), transplant rejection
antigen (haptin-carrier)-> APCs-> sensitized T-cells (CD4 Th1 and CD8 CTL)-> release cytokines (INF-g, TNF-a,b, IL-3), lymphokines, cytotoxicity -> macrophages-> destruction
24-72 hour delay
Goodpasture syndrome
Type II hypersensitivity
nephritis and lung hemorrhages
auto-immune to Type IV collagen in basement membranes of glomeruli and lung aveoli
Acute Rheumatic fever
Type II hypersensitivity
Antibodies against Strep cross-react with heart
Carditis
Serum Sickness
Type III hypersensitivity
rxn to large quantities of foreign protein
occurs 7-10 days after exposure (switch from IgM to IgG)
flu-like, urticarial rash, arthritis, glomerulonephritis
Complexes form most when antigen is no longer in extreme excess, closer to equilibrium only.
Systemic Lupus Erythematosus (SLE)
Type III hypersensitivity
antibodies against DNA or other nuclear things
arthritis, glomerulonephritis, skin disease
Lumpy deposition of complexes in these areas
Acute Inflammation
Infxns, trauma, chemical agents, necrosis, foreign bodies, hypersensitivities
TLR->cytokines, TNF->leukocytes / Inflammasome(dead cells)->caspase->IL-1->leukocytes
Vascular: histamine, NO-> stasis, leukocytes / histamine,bradykinin->endothelial cell contraction –>edema
Morphology: lots of neutrophils
Leukocyte Recruitment
Margination: accumulation at vessel periphery
Rolling: weak adhesion to endothelium (integrins, selectins)
Adhesion: firmer (integrins)
Transmigration (diapedesis): move through endothelium (PECAM, CD31)
Chemotaxis: move toward injury site (chemokines, ECM)
Leukocytes recognize opsonins, phagocytose-> ROS-> release degridative enzymes
Mediators of Inflammation
Histamine- vasodilation, vascular permeability- mast cells, basophils, platelets
NO- vasodilation, tissue damage- endothelium, macrophages
Bradykinin- vascular permeability, pain- plasma (liver)
IL1, TNF- chemotaxis, leukocyte recruitment, fever- macrophages, endothelial cells, mast cells
ROS- tissue damage- leukocytes
Serous Inflammation
Mildest acute inflammation
thin (protein poor) fluid (blister)
effusions, blisters
Fibrinous Inflammation
More severe
larger vascular leaks-> fibrin
affects linings (meninges, pericardium, pleura)
may resolve or lead to scarring
Suppurative Inflammation
purulent large # of neutrophils liquefied=pus pyogenic bacteria (Staph) Abscess
Ulcer
Local defect
sloughing of surface covering and necrotic inflammatory tissue
Chronic Inflammation
Persistent infxns (TB), prolonged toxin exposure, autoimmune disease, foreign bodies (silica)
Macrophages persist
Cytokines, IFN-g
Adaptive immune response is activated
Morphology: mononuclear cells (macrophages, lymphocytes, plasma cells),, tissue destruction, angiogenesis, fibrosis
Granulomatous Inflammation
Chronic inflammation TB, syphilis, silica, sarcoidosis inert foreign bodies,, immune rxn Multinucleated giant cells (INF-g) surrounded by fibrosis TB: central caseous necrosis
Systemic Effects of Inflammation
Acute phase rxn / SIRS
fever (pyrogens (LPS, IL1, TNF, PGE2)
elevated acute-phase proteins (via IL6,, C-reactive protein, fibrinogen–> elevated ESR, erythrocyte sedimentation rate)
leukocytosis (via TNF,IL1,, increased WBC
–Neutrophilia: bacterial (left-shift)
–Lymphocytosis: viral
–Eosinophilia: allergies, asthma, parasites
Extracellular Matrix
Interstitial matrix: 3D amorphous gel
Basement membrane: highly organized around epithelial, endothelial, smooth muscle cells
Provides scaffold for healing, stores growth factors, creates microenvironment
Collagen and elastin,, proteoglycans and hyaluronan,, adhesive glycoproteins and receptors
Ehlers-Danlos Syndrome
Genetic defect in collagen synthesis or structure
tissues lack tensile strength, hyperextensible, fragile
Tissue repair / scar formation
Angiogenesis (VEGF, NO, FGF)
fibroblast migration and proliferation (TGF-B, PDGF, FGF)
ECM deposition
maturation/remodelng of fibrous tissue
Granulation tissue= present by 3-5 days, contains new vessels, inflammatory cells, fibroblasts, collagen
Healing by First Intention (Primary union)
uninfected surgical incisions
clotting, then neutrophils, then macrophages and granulation tissue, then collagen, then scar w/o inflammation
Healing by Secondary Intention (Secondary Union)
More extensive damage, abscesses, ulcers
Large fibrin clot, more necrosis, large granulation tissue
Wound contraction= myofibroblasts
Substantial scar with thinned epidermis
Wound healing complications
Dehiscence: re-opening of the wound
Ulceration: lack of closure (often due to lack of angiogenesis)
Keloid: excessive collagen
Exuberant Granulation: open wound
Desmoid: Excessive fibroblasts (low-grade neoplasm)
Contractures: Scar gets too tight
Alcoholic cirrhosis
Lots of collagen with nodules of regenerating hepatocytes, loss of normal structure and function
ECM damage
Allograft rejection
major target= MHC (HLA: 6xClass I, 6xClass II)
MHC matching less important for solid organ, more important for hematopoietic stem cell
Minor HCs also important sometimes
Direct: T-cell recognizes unprocessed allogenic MHC
Indirect: T-cell recognizes processed peptide of allogenic MHC bound in host MHC
Hyperacute: due to pre-formed antibodies (xenotransplantation),, complement activation, endothelial damage, inflammation
Acute: Mostly T-cell mediated,, endothelialitis, interstitial damage
Chronic: months or years, macrophages, smooth muscle proliferation, vessel occlusion
Hematopoietic Stem Cell Transplan (HSCT)
therapy for malignancies, aplastic anemia, and immune deficiencies
First, chemo or radiation to eliminate bad HSCs, then new ones delivered IV
Graft rejection:
Graft vs Host:
Graft vs Tumor: donor T-cells kill residual tumor cells
Mixed Lymphocyte reaction
Assay for T-cell reactivity for transplant
Mix blood mononuclear cells from two donors in tissue culture, see if they react
HIV Transmission
Enters through open cuts, direct injection, mucus membranes (rectum, vagina, mouth)
via blood, semen, vaginal secretion, breast milk
Highest risk via blood, then semen, then vaginal, none by saliva
Receptive anal intercourse the most risk bc rectum only one cell thick (after needle sharing and mom-baby)
HSV and syphilis increase risk (bc activated t-cells)
genetic factors like CCR5 decrease risk
Uncircumsized=higher risk
Acute HIV infxn
symptoms begin 1-4 weeks following exposure, last for 2 weeks
test + for HIV RNA, but can be - for HIV antibodies
fairly non-specific symptoms, fever, sore throat, diarrhea, rash
Immune Reconstitution Inflammatory Syndrome (IRIS)
paradoxical deterioration in clinical status after initiating antiretroviral therapy due to the recovery of immune response to latent or sub-clinical infxns
AKA IRD or immune rebound illness
develops within 8 weeks of starting ART
happens with rapid improvement in immunologic or virologic parameters
HIV pathogenesis
Increases risk of many other things, incl heart disease
GALT is where most T-cells lost
GI disturbances due to gut permeability increase
chronic immune activation, even with long-term suppression
Prognosis dependent on viral load “set point” and CTL response
Uses conformational masking to evade immune antibody response
