Term
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Definition
| DNA sequence at a give locus |
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Term
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Definition
| outward, physical appearance |
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Term
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Definition
same locus, same gene, different sequence
-one from mom and one from dad
-Polymorphism-2 or more alleles (of the same gene) that occur in noted frequency |
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Term
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Definition
| genes at the same locus are identical |
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Term
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Definition
| genes not identical at same locus, so have two alleles |
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Term
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Definition
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Term
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Definition
| biochemical, molecular and cellular mechanisms of disease development |
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Term
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Definition
| functional consequences leading to the signs/symptoms (S/Sx) observed in the patient |
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Term
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Definition
| Virtually all forms of organ injury start with molecular or structural alterations in CELLS! |
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Term
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Definition
Movement
Conductivity
Metabolic Absorption
Secretion
Excretion
Respiration
Reproduction
Communication |
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Term
| INTERcellular communication |
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Definition
Function: maintain homeostasis
-Regulate growth and division
-Communication through chemical signals
-Transmission of electrical signals |
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Term
|
Definition
Change in DNA sequence that can result in abnormal DNA, RNA, and protein synthesis
Types
-Endogenous: spontaneous, metabolic activity
-Exogenous/environmental: radiation, smoking, UV light
Silent mutations: cause no change in phenotype |
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Term
| Types of cellular communication |
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Definition
Contact dependent
Paracrine
Autocrine
Hormonal
Neurohormone secretion
Neurotransmitter |
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Term
| Possible outcomes of DNA mutation |
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Definition
Repair by DNA repair mechanisms
Cell dysfunction (pre-senesence)
Malignant transformation
Cell death by apoptosis |
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Term
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Definition
10,000-1,000,000 lesions/day
If DNA damage exceeds capacity to repair, early senescence, apoptosis, or cancer
May genes initially shown to influence life span now shown to be involved in DNA repair and protection |
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Term
|
Definition
Autosomal recessive: requires aa with a being the disease causing allele: Aa is carrier
Autosomal Dominant: can get disease wiht AA or Aa, with A being the disease causing allele
X-linked disease: female carrier; male disease
Carrier: disease-causing allele is in their genotype (Aa), but they're phenotypically normal |
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Term
| Signal transduction: Intercellular events-responses |
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Definition
Channel opening
Change in electrical activity in the cell
Enzyme activation
Trafficking
Gene activation |
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Term
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Definition
multifactorial: interplay between genes and environment
polygenic: multiple genes involved...not just one |
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Term
| Etiology of cellular injury |
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Definition
Hypoxia
Reactive oxygen species and oxidative stress
Chemical agents and drugs
Infectious agents
Immunologic reactions
Physical agents
Genetic mutations and epigenetic derangements
Nutritional imbalances
Aging?? |
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Term
| Cellular adaptations to stress and injury |
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Definition
normal
atrophy
hypertrophy
hyperplasia
metaplasia
dysplasia |
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Term
| Common targets of cellular stress and injury |
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Definition
CELL MEMBRANE
Aerobic respiration (production of ATP)
Synthesis of enzymatic and structural proteins
Genetic apparatus
Intracellular calcium homeostasis |
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Term
| Hypoxia: clinical settings |
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Definition
Ischemia: loss of arterial blood supply
Inadequate oxygenation
Loss of the blood’s oxygen-carrying capacity |
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Term
| Hypoxic injury: reversible cell injury |
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Definition
Decreased oxygen affects mitochondrial ATP production:
-increased anaerobic glycolysis
-lactic acid accumulation leads to decreased pH
-poor myocyte contractile function
-impairment of cell volume regulation by the plasma membrane
Disruption of ribosomal interactions with the ER leads to decrease protein synthesis |
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Term
|
Definition
Changes in gene expression caused by mechanisms OTHER THAN changes in DNA sequence
-environmental factors (diet, chemical exposure) can cause epigenetic modifications
-maintained in successive mitotic cell divisions
-but most erased from genome when new gametes formed by meiosis |
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Term
| Types of epigenetic modifications |
|
Definition
DNA methylation:Methyl group added to the C of DNA.
-can either overreact or underreact.
Histones can be modified
-these determine the shape of the chromatin, so affects access of the gene
RNA-based mechanisms:
-decrease the gene expression |
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Term
| Impairment of cell volume regulation |
|
Definition
failure of Na+/K+ pump
intracellular Na+ accumulation
water diffuses to inside of cell -->
cell swelling/organelle swelling |
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Term
|
Definition
Subcellular alterations:
-Swelling of intracellular organelles
-Lysosomal membrane injury
Intracellular accumulations of normal cell constituents or toxic substances
Pathologic increase in cytosolic Ca2+ -> enzyme activation
ATP depletion and failure of cell processes
Death by necrosis |
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Term
|
Definition
Death by injury/disease -> ↑release of intracellular contents (some toxic)
Inflammatory response (can extend the damage)
Debris phagocytized or calcified |
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Term
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Definition
| Imbalance between production of reactive oxygen species (ROS) and antioxidant defenses |
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Term
| Physiologic role of epigenetic disease |
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Definition
Important in embryogenesis to turn genes on/off cell differentiation
Exercise --> ↓methylation --> structural/metabolic skeletal muscle changes
Remember: ALL cells have ALL genes, BUT … only certain genes are turned on --> specific cell morphology and function |
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Term
| Epigenetic modifications and disease |
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Definition
Cancer
-Hypermethylation -> “good” gene off (tumor suppressor)
-Hypomethylation -> “bad” gene stays on (oncogene)
Heart disease
-Hypomethylation ↑smooth muscle cell proliferation
-Hypomethylation ↑ WBC and inflammation
Aging process
-Both hyper and hypomethylation contribute |
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Term
|
Definition
Not all tumors are malignant..many are benign
Big Difference (hallmarks):
-Anaplasia: “without form” referring to loss of differentiation
-Metastasis: spread beyond tissue of origin |
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Term
|
Definition
An atom or group of atoms that has one or more unpaired electrons in its outer orbit
Extremely reactive and unstable
Aggressively interact with other compounds
-lipid molecules in cell membranes
-nucleic acids in the cell |
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Term
| Mechanisms of cell injury |
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Definition
Membrane damage
-Increased membrane rigidity
-Altered permeability
-Decreased membrane-bound enzyme fxn
-Altered activity of membrane receptors
Protein damage
DNA damage
Tissue damage and inflammation |
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Term
|
Definition
Direct: combine with essential cell components
Indirect: Converted to reactive toxic metabolites by liver and other organs |
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Term
|
Definition
Pathway induced by tightly regulated suicide program
Very different than necrosis
Physiologic events involving unwanted, aged, or harmful cells:
-Programmed cell death during embryogenesis
-Hormone-dependent involution
-Removal of self-reactive T cells |
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Term
|
Definition
pathologic atrophy of hormone-dependent tissues when hormone is absent
pathologic atrophy in organs after duct obstruction (e.g. pancreas, parotid gland, and kidney)
cell death (of virally infected cells) induced by cytotoxic T cells
cells with DNA damage
cells with misfolded proteins as seen in neurodegenerative disorders like Parkinson’s and ALS |
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Term
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Definition
DNA -> genes -> chromosomes
Histone proteins -> compressed coiling
22 autosomal pairs + 1 pair sex = 23 pair or 46 chromosomes
Regulates gene expression by controlling transcription factor access |
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Term
|
Definition
Basic unit of inheritance
Function: blueprint for proteins through transcription and translation
Influence all aspects of body structure and function
Human genome: 20,000-25,000 genes |
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Term
|
Definition
Transformation: normal cell becomes a cancer cell
Disease of aging:
-Multiple genetic “hits” overwhelm DNA repair mechanisms clonal expansion of mutated cell
-A stepwise accumulation of mutations in specific genes can occur and often involve:
--Proto-oncogenes
--Tumor suppressor genes |
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Term
| Cell with significant DNA damage |
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Definition
enter an irreversible state of dormancy
activate apoptosis and commit cell suicide
enter unregulated cell division ->malignant tumor growth |
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Term
|
Definition
Proto-Oncogenes: genes that encode proteins that promote normal cellular proliferation
-Once mutated, they become known as oncogenes
-Over-activation of oncogenes -> Unregulated growth
Tumor Suppressor Genes: genes that encode proteins that regulate (halt) cell proliferation
-Work in opposition to the proto-oncogene
-Mutations -> gene inactivation -> unregulated growth |
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Term
|
Definition
Recruitment of cells to alter microenvironment
Breakdown of any capsule
Angiogenesis |
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Term
| Functions of plasma proteins |
|
Definition
contribute to osmotic gradient between blood and ECF of interstitium
contribute to pH buffering capacity of plasma
bind and transport many substances
contribute to body defenses
contribute to blood clotting
regulatory substances |
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Term
|
Definition
Reduction of total circulating RBC mass reduced oxygen-carrying capacity of blood
Underlying Mechanisms:
-Blood Loss (acute or chronic)
-Decreased RBC production
-Increased RBC destruction |
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Term
|
Definition
Nutritional: dietary deficiency of factors
-Iron-deficiency
-Folic acid and B12 deficiency
Pernicious: deficiency of intrinsic factor -> decreased B12 absorption -> decreased RBC proliferation and maturation
Erythropoietin deficiency: renal failure with ↓ EPO
Cancers: leukemias, bone metastasis
Aplastic anemia: bone marrow failure (pancytopenia) |
|
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Term
| Increased RBC destruction |
|
Definition
Inherited genetic defects: Enzyme deficiencies -> ↑ ROS damage
Antibody-mediated destruction: hemolytic disease of newborn, transfusion reactions
Infections of RBC: malaria
Chemical injury: snake venom, Clostridium, lead poisoning
Sequestration: Hypersplenism
Hemoglobin abnormalities:
-Deficient globin synthesis: thalassemias
-Defective globin structure -> hemoglobinopathies |
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Term
| Sickle Cell Disease (SCD) |
|
Definition
| Inherited point mutation in beta globin chain |
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Term
|
Definition
Deoxygenation/dehydration -> HbS polymer stacking -> sickling
Microvascular occlusion -> infarction and pain
-Sickled RBC can’t deform well to transit the capillary bed ->
-Slow transit times -> ↑sickling
-More likely in areas of inflammation
May regain shape with oxygenation and rehydration
Some suffer irreversible membrane damage -> sickling and hemolysis
RBC membrane damage -> Ca2+ influx -> enzyme derangements |
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Term
|
Definition
Vascular Spasm
Platelet Plug Formation
Coagulation Cascades
Clot Retraction |
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Term
|
Definition
plasma proteins synthesized in the liver
Vitamin K-dependent factors:
-II, VII, IX, X, prothrombin
-Vit. K required for their function
circulate in an inactive state
operate in a cascade fashion
Activated via two major pathways |
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Term
|
Definition
Intrinsic factored by Endothelial damage is the root cause
XII -> active XII -->
XI ->
Extrinsic triggered by tissue damage
(See slide 22 & 23! to fill out) |
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Term
|
Definition
Major Types
-Absence of Factor VIII -> Hemophilia A (80-85%)
-Absence of Factor IX -> Hemophilia B
Genetics
-X-linked recessive trait:
--carried by females
--affects males and homozygous females
-Gene deletions or point mutations
Spectrum of hemorrhagic severity
-concentration of clotting factor in blood
-bleeding only after severe trauma to spontaneous hemorrhage
-Hemorrhage into joints -> pain, limited mobility and degeneration |
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Term
|
Definition
Function:
-prevent extensive clot formation beyond the site of injury during the coagulation phase
-provide clot lysis during the healing phase
Initiation:
-At time of injury, t-PA released from the endothelium
-t-PA converts plasminogen (in clot) to plasmin
Functions of plasmin:
-Degrades fibrinogen/fibrin -> Fibrin Degradation Products (FDPs)
-Inactivates clotting factors, including prothrombin |
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Term
|
Definition
Antithrombin III
Tissue Factor Pathway Inhibitor (TFPI)
Thrombomodulin
Protein C & Protein S |
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Term
|
Definition
Anticoagulation:
-maintain smooth, continuous vessel lining
-generation of physiologic anticoagulants (t-PA, prostacyclin, thrombomodulin, TFPI)
-site of antithrombin III, Protein S and Protein C anticoagulant activation and/or activity |
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Term
|
Definition
Etiology of endothelial damage
-inflammation and infection
-shock
-hypoxemia
-acidosis
endothelial damage -> disrupted hemostatic balance -> increased procoagulant activity -> DIC |
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|
Term
| Disseminated Intravascular Coagulation (DIC) |
|
Definition
DIC is not an independent entity but a secondary mechanism occurring in response to an underlying pathologic process
1. DIC is a serious coagulation disorder resulting from:
a) Accelerated coagulation
b) Excess thrombin generation ***Key pathogenic event
c) consumption of normal clotting components and platelets
d) excessive fibrinolysis
2. DIC is characterized by systemic microvascular thrombosis and generalized hemorrhage
3. Aka thrombohemorrhagic disorder |
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Term
| Clinical conditions leading to DIC |
|
Definition
Infections
Inflammation
Obstetric complications
Transplant rejection
Hemolytic/Immune
Neoplastic Disorders
Cardiovascular Disorders |
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Term
|
Definition
Inciting Event -> triggers clotting cascades and a procoagulant state
-Endothelial damage
-Tissue damage
-Infection or inflammation
Excess thrombin generation -> microvascular thrombosis (KEY)!!***
Alteration in Coagulation Components and Excessive Fibrinolysis --> Hemorrhage |
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Term
|
Definition
Destroy invading pathogens
Id and destroy foreign, abnormal or mutant cells
Removing dead cells and tissue debris |
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Term
| Pathologic immune activities |
|
Definition
Loss of regulation (sepsis, SIRS, allergy)
Recognition of self as nonself (autoimmunity)
Loss of function (immunodeficiency, oncogenesi |
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Term
| Nonspecific vs. specific immune responses |
|
Definition
Innate
-nonspecific response triggered by tissue insult or microbial invasion
-inflammation, WBC activation and tissue repair
Acquired/adaptive
-characterized by specificity and memory
-primarily involves B and T lymphocytes |
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Term
| Physiologic response to injury |
|
Definition
Triggering of the IIR
Neuroendocrine activation
Wound localization |
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Term
|
Definition
Plasma Protein Cascades
Cellular Elements
Biochemical Mediators |
|
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Term
|
Definition
Complement
Kallikrein/kinin
Coagulation
Fibrinolysis |
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Term
|
Definition
Triggered enzyme system
Triggered by:
antigen/antibody complexes (classic pathway)
microbes and cell debris (alternative pathway) |
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Term
| Functions of activated complement |
|
Definition
a. Target cell lysis via formation of the membrane attack complex, C5-C9.
b. Cellular attraction and activation of phagocytic cells (neutrophils and macrophages)
c. Opsonization - enhancement of phagocytosis by the deposition of opsonins (e.g. antibody or complement fragments) on the antigen
d. Induction of inflammation via increased microvascular permeability and vasodilatation |
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Term
|
Definition
Leads to
-Vasodilation
-Vascular permeability
-Pain |
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Term
|
Definition
all leukocytes originate from undifferentiated stem cells in the bone marrow
mediators govern the production rates of the various WBCs |
|
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Term
|
Definition
Polymorphonuclear granulocytes (PMNs)
Monocytes/Macrophages |
|
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Term
| Polymorphonuclear granulocytes (PMNs) |
|
Definition
Neutrophil - major circulating PMN
-(60-70% of total WBC)
-first circulating WBC to the scene
-primary role: phagocytosis***
-major source of potent biochemical mediators
Other PMNs: eosinophils & basophils. |
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Term
| Monocytes and macrophages |
|
Definition
make up 2-6% of total WBC
primary role: phagocytosis
Inflammatory Macrophages: monocytes migrate and differentiate into tissue macrophages during inflammation (i.e. monocytes become macrophages) |
|
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Term
|
Definition
(a) Kupffer cell - liver
(b) Alveolar macrophages - lung
(c) Microglia - CNS
(d) Langerhans - skin
(e) Dendritic cells - lymphoid tissue
(f) Osteplasts - bone marrow |
|
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Term
|
Definition
1. chemotaxis
2. attachment
3. phagocytosis
4. destruction |
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Term
|
Definition
| major link between innate and acquired responses via antigen processing & presentation |
|
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Term
|
Definition
(a) Kupffer cell - liver
(b) Alveolar macrophages - ung
(c) Microglia - CNS
(d) Langerhans - skin
(e) Dendritic cells - lymphoid tissue |
|
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Term
|
Definition
(1) NOT just the allergy cell anymore
(2) Located at interface of body and environment: skin, respiratory tract, GI tract, GU tract
(3) Serve as sentinels for invading pathogens
(4) Release of potent chemical mediators: preformed and synthesized following activation
(a) Degranulation of preformed mediators:
(b) Synthesis and release of newly formed mediators: |
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Term
|
Definition
T-lymphocytes
B-lymphocytes |
|
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Term
|
Definition
(1) Major effector cells of the specific immune response
(2) Distinguished by two characteristics: specificity and memory***
(3) Activation primarily takes place in lymphoid tissue: lymph node, spleen, airways, gut, oropharynx
(4) Make up 25 - 33% of total WBC. Increased in viral infections. |
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Term
| B-cell (humoral) immunity |
|
Definition
(1) generation and maturation in the bone marrow
(2) most reside in lymphoid tissue
(3) upon activation, differentiate into either
(a) plasma cells, which produce antibodies
(b) memory cells, which reside in the lymphoid tissue |
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Term
| T-cell (cell-mediated) immunity |
|
Definition
(1) major regulator of immune response
(2) generation in bone marrow, but maturation in the thymus
(3) most reside in lymphoid tissue
(4) different T lymphocyte subsets orchestrate the IIR
(a) CD4+ T cells (TH-Helper) - 60-80% of circulating T cells.
(i) TH1 - induce macrophage activation and additional T-cell activity
(ii) TH2 - produce cytokines that enhance B-cell proliferation, differentiation, and Ab production
(b) CD8+ T cells(Cytotoxic/CTL) - kill body cells “gone bad”
(i) virally-infected cells
(ii) tumor cells
(iii) intracellular parasites |
|
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Term
|
Definition
CD4+ (Helper) - 60-80% of circulating T cells
-TH1 - induce macrophage activation and additional T-cell activity
-TH2 - produce cytokines that enhance B-cell proliferation, differentiation, and antibody production
CD8+ (CTL) - kill body cells “gone bad”
-virally-infected cells
-tumor cells |
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Term
|
Definition
1. Cytokines-cellular messengers in the immune response; includes lymphokines & monokines (older terms)***
2. Others mediators include arachidonic acid metabolites (e.g. prostaglandins), proteases, reactive oxygen species, interferons, and nitric oxide.
3. Source:activated WBCs, platelets, endothelium
4. Primary function - establish physiologic changes necessary for the IIR, including vascular changes and anti-microbial activity |
|
|
Term
| Three levels of host defense function, interaction, activity |
|
Definition
natural defenses
nonspecific immune response
specific immune response |
|
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Term
|
Definition
1. Integumentary - mechanical barrier (intact skin), acid pH, enzymes, microbiome
2. Pulmonary – epithelial barrier, mucociliary escalator, cough/gag, IgA, macrophages, enzymes
3. Gastrointestinal – epithelial barrier, acid pH (stomach), microbiome, IgA, motility, mucous secretions, salivary and gut enzymes
4. Genitourinary - epithelial barrier, flushing, IgA, acidic pH, vaginal microbiome |
|
|
Term
|
Definition
|
|
Term
|
Definition
| Nonspecific response to tissue insult or invasion (mechanical, chemical, microbial, ischemic) |
|
|
Term
|
Definition
-Mobilize large numbers of neutrophils, monocytes, and plasma proteins to the areaProtect the host
-Limit the extent of injury
-Promote rapid healing |
|
|
Term
| Physiology of inflmmation |
|
Definition
Vasodilation
Increased microvascular permeability
Coagulation
WBC activation, adhesion, and mediator release |
|
|
Term
| Pattern recognition in innate |
|
Definition
Receptors on Neutrophils/Macrophages bind molecular patterns on targets
Receptor binding --> intracellular signaling
Activation of the IIR cell --> phagocytosis |
|
|
Term
| Pattern Recognition Receptors (PRRs) |
|
Definition
(1) Recognize pathogen-associated molecular patterns (PAMPs)
(a) On infectious agents or their products
(2) Recognize damage-associated molecular patterns (DAMPs)
(a) Products of cellular damage, necrosis or apoptosis
(b) Including chromatin, extracellular matrix proteins |
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Term
|
Definition
a. Engulfment of bacteria or other debris
b. Macrophages will carry out antigen processing and presentation of antigen to T lymphocytes (APCs) |
|
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Term
|
Definition
(a) Clean incision with minimal tissue loss and close apposition of wound edges
(b) Very little sealing and shrinkage needed |
|
|
Term
|
Definition
(a) large, open or dirty wounds
(b) Sealing and shrinking take much longer
(c) Much greater scarring |
|
|
Term
|
Definition
(1) Debridement during inflammatory phase (preliminary phase to prepare tissue for healing)
(a) Phagocytosis of particulate matter: fibrin, tissue debris, microbes, dead WBCs and RBCs
(b) Clot dissolution
(2) Reconstructive phase:
(a) Epithelialization
(i) Epithelial cells move in from edge of wound along with angiogenesis (new vessels)
(a) Matrix formation
(b) Formation of granulation tissue-bright, shiny red
(ii) Inward migration of fibroblasts
(a) Collagen synthesis and secretion
(b) Initially deposited randomly
(c) Continually remodeled over weeks/months → ↑ strength to wound matrix
(b) Wound contraction
(i) Inward movement of wound edges
(ii) Probably carried out by myofibroblasts bringing neighboring cells together
(iii) Interaction between new extracellular matrix and granulation tissue
(3) Maturation Phase
(a) Remodeling of scar tissue and removal of capillaries necessary for reconstruction
(b) Wound contraction continues |
|
|
Term
| Outcomes of acute inflammation |
|
Definition
Complete resolution
Fibrosis (healing by connective tissue replacement)
Abscess formation
Progression to chronic inflammation |
|
|
Term
| Principles of acquired immune response |
|
Definition
Characterized by specificity and memory
Antigen - substance bound by a specific antibody or T-cell receptor (TCR)
Each preformed lymphocyte is specific for only one antigen or antigen/MHC complex
Clonal expansion - Once the specific lymphocyte is activated by antigen binding, it rapidly reproduces forming tremendous numbers of duplicate lymphocytes known as clones (a family of lymphocytes expressing the same specificity). |
|
|
Term
|
Definition
a. B-cell binds specific antigen via surface receptors, which are identical to the soluble immunoglobulins (antibodies) that the B cell will eventually produce
b. B-cell grows and divides under the influence of TH2 cells, differentiating into plasma cells that produce specific antibodies to the antigen.
c. Antibodies function to:
(1) Bind specific antigen → possible neutralization of that antigen
(2) Activate & fix complement → increased phagocytosis and inflammation
(3) Opsonize particles → increased phagocytosis
(4) Function also depends on antibody class/isotype:
(a) IgM - involved in the primary response (1st exposure)
(b) IgG - produced in large quantities when the body has previously been exposed to a specific antigen
(c) IgE - mediator in common allergic responses
(d) IgA - found in mucous secretions
(e) IgD - function is uncertain
d. Antigen/Ab complex is phagocytized by neutrophil or macrophage
e. A small percentage of B cells of the same clonal family do not differentiate into antibody-producing plasma cells, but remain in lymph tissue as memory cells. |
|
|
Term
|
Definition
a. Helper function
(1) Helper T cell (CD4+) is presented with foreign antigen in association with MHC by antigen-presenting cell (APC)
(2) TH cell receptor binds with {Antigen + MHC II} on APC → T cell activation and proliferation
(3) TH cell produces cytokines that
(a) enhance B-cell proliferation, differentiation, and antibody production
(b) macrophage activation
(c) additional T-cell activity
b. Cytotoxic function (CTL)
(1) Cytotoxic T-cell (CD8+) recognizes {Ag + MHC I} usually on a virally-infected cell or a tumor cell
(2) The T cell receptor binds with the antigen/MHC I on the abnormal cell
(3) CTL releases substances (perforin, granzymes) that cause cell death of the abnormal target cell
4. Acquiring long-term immunity
a. occurs only via the acquired, specific response
b. memory cells may be established via natural exposure (infection) or artificial exposure (vaccination)
c. subsequent responses are swifter, stronger, and more specific |
|
|
Term
|
Definition
Bind specific antigen --> possible neutralization
Activate complement --> increased phagocytosis and inflammation
Opsonize particles --> increased phagocytosis
Function depends on antibody class/isotype |
|
|
Term
| Immunosuppression in neonate and young children |
|
Definition
1. Compromised external barriers
a. Thinner skin
b. Lower stomach acidity
c. Diminished sweat and sebaceous gland production
2. Fewer stored neutrophils/kg
3. Altered neutrophil chemotactic and phagocytic functions
4. Decreased ability to present antigen to T cell
5. Lower complement levels
6. Lower antibody levels |
|
|
Term
| Immunosuppression in the elderly |
|
Definition
1. Compromised external barriers
a. Thinner skin
b. Blunted cough and laryngeal reflexes
c. Decline in gut lymphoid tissue size and function
d. Decreased gut motility and gastric acid secretion
2. Decreased protein production by the liver
3. Decreased neutrophil, monocyte, and lymphocyte counts and activity
4. Overall decrease in cell-mediated and humoral immunity
5. Decreased antibody and cytokine production |
|
|
Term
|
Definition
Physiologic
-Fever
-Leukocytosis
-Increase in acute phase reactants
-Drowsiness, malaise, anorexia, muscle aches
Pathophysiologic
-Systemic Inflammatory Response Syndrome (SIRS) |
|
|
Term
| Similarities between immunosuppression in young and elderly |
|
Definition
Natural defenses
Innate (nonspecific) responses
Acquired (specific) responses |
|
|
Term
|
Definition
1. Fever: temporary resetting of hypothalamic set point to a higher level (Fig. 16-8)
(a) Triggered by the action of circulating pyrogens
(i) Exogenous pyrogens: Microbial products (e.g. endotoxin)
(ii) Endogenous pyrogens: Cytokines (e.g., TNF, IL-1, PGE2)
(b) Body feels “cold” and triggers heat production→
(c) Antipyretics return setpoint to normal and fever “breaks”
(i) Acting directly on the hypothalamus or decreasing production of endogenous pyrogens such as prostaglandins
(ii) Body feels hot and patient throws covers off and sweats
(d) Benefits of fever
(i) Kills or adversely affects growth of microbes
(ii) Increases proliferation and activity of WBCs
(iii) Lysosomal breakdown →autodestruction of virally-infected cells
(iv) Decreases levels of cations (iron, zinc, copper) needed for bacterial replication |
|
|
Term
|
Definition
a. Increase in circulating leukocytes
b. Triggered by cytokines and growth factors
c. Often accompanied by a “left” shift” (more immature neutrophils) |
|
|
Term
| Increase in acute phase reactants |
|
Definition
a. Most produced by liver in response to IL-1 and other cytokines
b. Include fibrinogen, C-reactive protein (CRP), transport proteins, clotting factors, complement
4. Drowsiness, malaise, anorexia, muscle aches (many caused by cytokines like TNF) |
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Term
| Pathophysiologic effects of IIR |
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Definition
1. Systemic Inflammatory Response Syndrome (SIRS)
a. Represents loss of regulation of the IIR
b. Triggered by multiple insults including infection, injury/inflammation, and ischemia
2.Ex aggerated response with overwhelming mediator Release → Pathophysiologic Changes
3. Septic shock |
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Term
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Definition
Loss of IIR regulation
A. Contact with antigen can lead to reactions that damage tissues. These antigens can be exogenous → allergic responses or endogenous → autoimmunity.
B. Types of Hypersensitivity Reactions (Table 9-3) |
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Term
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Definition
B. Type I reactions
1. Include hives, asthma, hay fever, food allergies, and anaphylaxis.
2. Initial phase - 5 to 30 min after exposure to the antigen
a. Triggered by IgE-mediated mast cell degranulation
b. vasodilatation, vascular leakage, smooth muscle spasm, glandular secretions
c. often subsides within 60 min if antigen is removed
3. Late phase - 2-8 hours later
a. more intense infiltration of tissues with eosinophils, neutrophils, basophils, and monocytes
b. also, tissue destruction of the mucosal epithelium
C. Type IV reactions (also known as delayed-type hypersensitivity reactions [DTH])
1. include contact dermatitis, e.g., poison ivy and insect venom
2. mature response appears 24-48 hours after exposure as effector cells such as macrophages are drawn into the area by cytokines released by sensitized T cells
Type I and II are more common with allergy, types II, III, and sometimes IV associated with autoimmune. |
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Term
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Definition
A. Immunologic tolerance: lack of immune responsiveness to a specific antigen
B. Self-tolerance: a state of immunologic tolerance involving lack of responsiveness to one’s own tissues
C. Basis for self-tolerance
1. clonal deletion - loss of self-reactive T and B lymphocytes during their maturation
2. clonal anergy - functional inactivation of lymphocyte induced by encounter with antigen under certain conditions, e.g., lack of costimulation. May occur in bone marrow, thymus, or out in periphery
3. peripheral regulation - factors in the periphery that may serve as a fail-safe mechanism if the primary mechanisms of clonal deletion and anergy fail. May include Treg activity [regulatory T cells] |
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Term
| Background on autoimmune disorders |
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Definition
A. Facts & Figures
1. Over 80 different disease states
2. Affect ∼ 5-8% of the population
B. Predisposing Factors - susceptibility is complex and multifactorial. Most likely, environmental factors trigger pathologic autoimmune responses in those genetically predisposed.
1. Gender - female predominance. Onset often linked with puberty, pregnancy, and menopause
2. Race - susceptibility differs from disease to disease
3. Genetic susceptibility – often associated with HLA region on Chromosome #6
4. Environment
a. toxins
b. infectious agents, particularly viral
c. drugs
d. geographic and seasonal factors
e. stress
C. Classification
1. Organ-specific - characterized by immune responses directed against a single tissue or protein
a. Immunopathogenic mechanism: often Type II hypersensitivity responses
b. Many are endocrine diseases, e.g., Grave’s Disease
2.Systemic (multisystem) - characterized by immune responses against numerous organs or at multiple sites, commonly kidney, joints and skin
a. Immunopathogenic mechanism: often Type III hypersensitivity responses
b. Associated with a variety of autoantibodies → immune complex deposition
c. Many are connective tissue diseases and are sometimes referred to as the rheumatological disorders, e.g., SLE, rheumatoid arthritis, scleroderma |
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Term
| Classification of auto immune disorders |
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Definition
1. Organ-specific - characterized by immune responses directed against a single tissue or protein
a. Immunopathogenic mechanism: often Type II hypersensitivity responses
b. Many are endocrine diseases, e.g., Grave’s Disease
2. Systemic (multisystem) - characterized by immune responses against numerous organs or at multiple sites, commonly kidney, joints and skin
a. Immunopathogenic mechanism: often Type III hypersensitivity responses
b. Associated with a variety of autoantibodies → immune complex deposition
c. Many are connective tissue diseases and are sometimes referred to as the rheumatological disorders, e.g., SLE, rheumatoid arthritis, scleroderma |
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Term
| Overview of patho of autoimmune |
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Definition
1. Autoimmunity is a form of hypersensitivity and thus is often classified according to the same “Type” system. All types of hypersensitivity reactions are observed in autoimmunity except Type I.
a. antibody to surface or matrix antigens (Type II)
b. immune complex disease (Type III)
c. T-cell mediated disease (Type IV)
2. The immunopathology of autoimmune disease is mediated by sustained SPECIFIC responses (T & B lymphocytes) to self-antigens, although cells of the innate immune response (such as neutrophils and macrophages) may play a role in contributing to inflammation and tissue damage. |
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Term
| Organ-specific autoimmune pathologies |
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Definition
Type II-like response
1. Autoantibodies
a. directed against antigens on the surface of specific cells or tissues
b. thus damage is localized to tissue site of antibody binding
c. tissue antigens often include cell surface receptors such as TSH receptors (Grave’s disease) or acetylcholine receptors (Myasthenia gravis)
2. Cell-mediated responses by autoreactive T cells “helping” B cell antibody production |
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Term
| Systemic/multi-system autoimmune pathologies |
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Definition
Type-III like responses
1. Autoantibodies
a. directed against widely distributed SOLUBLE antigens -->
b. formation of many immune complexes (Ag/Ab complexes) -->
c. deposition at various sites (e.g., kidneys, joints, skin) throughout the body -->
d. inflammation via complement activation and/or phagocyte activation
2. Site of deposition of immune complexes secondary to:
a. increased permeability of vasculature
b. site of increased BP and turbulence
(1) glomerular capillaries
(2) ciliary body of the eye
c. charge of the complex
d. size of complex
e. immunoglobulin (Ig) class |
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Term
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Definition
1. Initiated by T cells, both CD4+ and CD8+, often leading to chronic inflammation
2. May induce either
a. organ-specific autoimmune disease – Multiple sclerosis, Type I diabetes
b. systemic autoimmune disease – Rheumatoid arthritis, Sjogren’s syndrome |
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Term
| Theories to explain loss of self-tolerance |
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Definition
A. Genetic predisposition → breakdown of self tolerance
B. Environmental triggers →promote activation of self-reactive lymphocytes
1. Drugs or toxins → bind tissue → altered tissue structure, such that tissue is seen as “foreign”
2. Infections
a. Upregulation of immune molecules → breakdown of anergy
b. Molecular mimicry -antibodies to infectious agents cross react with self-tissues
c. Polyclonal lymphocyte activation
(1) Microbes and/or their products non-specifically stimulate multiple clones of B cells.
(2) This may include self-reactive B cells that were previously anergic/non-reactive
C. Diminished Treg activity → failure of peripheral immunoregulation |
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Term
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Definition
1. organ-specific (Type II)
2. autoantibodies against the acetylcholine receptor at the neuromuscular junction --> blockage of receptor or decreased receptors (receptor antagonism)
3. neurotransmission is impaired --> voluntary muscle weakness and fatigue |
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Term
| Graves' Disease (Hyperthyroidism) |
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Definition
1. organ-specific (Type II)
2. autoantibodies against the TSH receptor on thyroid → activation of the receptor (receptor agonism)
3. receptor activation → hypertrophy and hyperplasia of thyroid cells and overproduction of T3 and T4 |
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Term
| Systemic Lupus Erythematosus (SLE) |
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Definition
1. systemic (Type III)
2. autoantibodies present against an array of nuclear and cytoplasmic components of the cell
3. high immune complex deposition in small blood vessels, kidneys, connective tissue (joints) and skin
4. course of disease is variable and is characterized by exacerbations and remissions.
5. severe complications include renal failure, infection, and CNS disease |
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Term
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Definition
1. Type IV disease involving T cells that target myelin proteins → demyelination and plaque formation
a. Plaques contain T cells and macrophages attracted by the T cell’s cytokines
b. Activated neutrophils and macrophages and their toxic products → myelin breakdown (demyelination)
c. Axons degenerate and local astrocytes cause scarring (gliosis)
2. Nerve conduction is slowed and ultimately ceases |
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Term
| General features of immunodeficiencies |
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Definition
1. Major consequence of immunodeficiency is increased susceptibility to infection
a. defective humoral immunity --> increased susceptibility to bacterial infections
b. defective cell-mediated immunity --> increased susceptibility to intracellular pathogens such as viruses and TB
2. Patients with T-cell immunodeficiencies are prone to certain types of cancers, many of which are associated with oncogenic viruses
3. May involve any of the components of the specific or nonspecific immune response |
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Term
| Primary (Congenital) Immunodeficiencies |
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Definition
1. Most are genetically determined
2. Affect specific or nonspecific immune responses
3. Most manifest themselves in infancy
4. Examples
a. agammaglobulinemia
b. severe combined immune deficiencies |
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Term
| Secondary (Acquired) immunodeficiencies |
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Definition
1. May or may not have a genetic component
2. Environmental factors play a major etiologic role
a. infections, particularly viruses, e.g., HIV
b. malnutrition
c. aging
d. stress
e. side-effects of therapeutics |
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