patho exam 1

pathology

The causes of

disease and the changes in

cells, tissues, and organs that

are associated with

development of disease

etiology

the origin of a

disease, including the

underlying causes and

modifying factors

pathogenesis

steps in

disease development

homeostasis

steady state of

steady internal physical and

chemical conditions

adaptation

cell adjusts and survives in new steady state

reversible injury

homeostasis is restored

irreversible injury

leads to cell death; permanent

oxidative stress

Harms membranes, proteins, DNA.

Normally controlled by enzymes (catalase, glutathione peroxidase).

endoplasmic reticulum stress

• This process is imperfect, and some misfolded

polypeptides are generated

Misfolded proteins in the ER activate the

unfolded protein response (an adaptive

response) via sensors like IRE1

• UPR increases chaperone expression, reduces

protein synthesis, and increases protein

buildup of misfolded proteins.

Mild = adaptive (helps refold/remove proteins).

Severe = triggers apoptosis.

ER stress injuries

Misfolded proteins can accumulate inside cells due to two main reasons: an increase in their production or a decrease in the body's ability to eliminate them. Factors contributing to this problem include:

- Genetic mutations in the proteins, or in the unfolded protein response (UPR) pathway

- Aging

- Viral infections

- Changes in intracellular pH and redox state

- Conditions like hypoxia and ischemia

These misfolded proteins can lead to disease in several ways: they can result in a shortage of essential proteins (loss of function), trigger programmed cell death (apoptosis), or acquire harmful properties (gain of function). For example, mutations in proteins can cause disorders like cystic fibrosis.

ubiquitin proteasome system

cell’s garbage disposal / recycling system.

It removes proteins that are damaged, misfolded, or no longer needed.

ubiquitin ligases attach to ubiquitin to the protein that needs to be destroyed

distribution of ca homeostasis

too much Ca²⁺ inside → activates enzymes that damage membranes, cytoskeleton, etc.

cellular adaptation to stress

Reversible changes in the number, size, phenotype, metabolic

activity, or functions of cells in response to changes in their

environment

physiologic adaptations

the responses of cells to normal stimulation by

hormones or endogenous chemical mediators, or to the demands of

mechanical stress

ex: enlargement of ovary during pregnancy

pathological adaptations

the responses to stress that allow cells to

modulate their structure and function and thus escape injury, but at the

expense of normal function

ex: hypertrophy of the heart in response to increased orkload

hypertrophy

Increased cell size leads to increased organ size, but no increase

in cell number

• Can progress to cell injury if the stress is not relieved or if it

exceeds the adaptive capacity of the tissue

hyperplasia

Increase in number of cells in an organ; increased proliferation
• Hyperplasia can be physiologic or pathologic

Physiologic hyperplasia

Hormonal: proliferation of the glandular epithelium of the female breast
at puberty and during pregnancy
• Compensatory: residual tissue grows after removal or loss of part of an
organ

pathologic hyperplasia

Endometrial hyperplasia: increased uterine epithelial proliferation due to

increased estrogenic stimulation

• Benign prostatic hyperplasia: disruption of androgens and estrogens

leads to hyperplasia in the prostate

atrophy

Reduced size of an organ or tissue caused by reduction in the

size and number of cells due to both pathologic and physiologic

causes

Atrophy results from a combination of decreased protein

synthesis and increased protein degradation (UPS)

• Atrophy is often accompanied by increased autophagy

metaplasia

A change in which one adult cell type is replaced by
another adult cell type
• Typically arises from reprogramming of stem cells rather
than phenotypic change of differentiated cells

High risk of malignant transformation: If the stimulus that

induces metaplasia persists, this can lead to malignant

transformation and the development of cancer

mechanisms of cell injury and cell death

• Causes: low oxygen, toxins, infections, physical/chemical damage.

• Reversible injury: swelling, fatty change (esp. liver).

• Irreversible injury: cannot restore mitochondria or DNA; membranes and proteins destroyed.

Key damage points:

• Mitochondria → less ATP, more ROS → apoptosis.

• Membranes → leaks, swelling, enzyme release.

• DNA → if badly damaged, p53 triggers apoptosis.

cellular swelling

Increased cell size and swollen organelles

• Accumulation of degenerated organelles and

lipids within injured cells

• Gross morphology: Pallor, turgor, increased

organ weight

• Microscopic changes: hydroponic change,

vacuolar degeneration

• Commonly seen when cells are injured by

hypoxia and other causes that deplete ATP

fatty changes

Lipid vacuoles in cytoplasm

• Common in organs involved in lipid

metabolism (liver)

mitochondrial dysfunction and damage

Decreased ATP generation and depletion of ATP in cells leads to:

• Reduced activity of plasma membrane ATP-dependent sodium pumps leads to

cellular swelling and dilation of ER

• Compensatory increase in anaerobic glycolysis leads to lactic acid

accumulation, decreased intracellular pH, and decreased activity of many

cellular enzymes

• Prolonged ATP depletion leads to structural disruption of the protein

synthetic apparatus

• Detachment of ribosomes from rough ER, dissociation of polysomes, reduction

in protein synthesis

Mitochondrial membranes

formation of mitochondrial

permeability transition pore

Plasma membranes:

loss of

osmotic balance, influx of fluids

and ions, loss of cellular contents

Lysosomal membranes

leakage

of enzymes into cytosol

Dystrophic calcification

in dead/damaged tissue.

Extracellular Deposits: Pathologic

Calcification

the result of abnormal deposition of calcium salts; fine white

granules or clumps and gritty deposits

Dystrophic calcification

deposition of crystalline calcium phosphate

in membrane-bound vesicles

Dna damage

mutations in mitochondrial and nuclear DNA

accumulate with age and cause the following

Cell aging

Certain environmental stresses, such as

calorie restriction, alter signaling pathways that influence aging,

including insulin-like growth factor (IGF-1) and molecular target of

rapamycin (mTOR) signaling

Telomeres = “caps” at chromosome ends that shorten with age.

Persistent inflammation:

accumulation of damaged cellular

components can activate the pathways that cause low-level

inflammation

difference between apoptosis and necrosis cell death

mictochondrial intrinsic pathway (apotosis)

Most physiologic and

pathologic situations

programmed, neat, no inflammation

extrinsic pathwway apoptosis

Controlled by death

receptors (TNF

receptor family and

Fas)

• When ligand binds,

receptors cross-link via

death domain and bind

adapter proteins

• Leads to the activation

of caspase cascade

caspase cascade

Degradation of cellular

proteins and nuclear

fragmentation

• Apoptotic cells recruit

phagocytes that

clearance of apoptotic

bodies

• No inflammatory

response

autophagy

“Self-eating:” lysosomal

digestion of a cell’s own

components

• Recycling mechanism during

nutrient deprivation

• Organelles and portions of

cytosol are sequestered in

membrane-bound

compartments

• Autophagosome fuses with

lysosome, where enzymes

digest cellular components

Metastatic calcification

in normal tissue due to high blood calcium.

necrosis

accidently, messy, causes inflammation (cell death)

hypoxia

low o2

ischemia

no blood flow, worse than hypoxia because its faster cell death

restoring blood flow causes even more damage

direct toxins are direct, indirect need conversion

primary lympahtic organs

bone marrow, thymus, fetal liver (maintain immune system)

secondary lymphatic organs

spleen, lymph nodes, lymph ducts, tonsils, adenoids

lymphatic vesesels

-part of the circulatory system; network of vessels

–carry clear fluid (lymph) towards the heart

–transports immune cells (lymphocytes; MP)transports immune cells (lymphocytes; MP

first line of immune defense

physical barriers (skin/epithelial

barriers; mucous membranes) and chemical barriers

second line of immune defense

Innate immune system

nonspecific immediate response (phagocytic cells,

inflammatory response, antimicrobial proteins,

complement, natural killer/NK cells)

third line of immune defense

Adaptive immune system specific

slower response; provides improved recognition;

immunological memory- faster recognition & stronger

secondary response (B and T lymphocytes)

innate immune system

– Phagocytes: monocytes, macrophages (MP),

neutrophils

– Mast cells, eosinophils, basophils

– Natural killer (NK) cells, innate lymphoid cells (ILC)

body’s rapid non specific first line of defense, immediate but general protection against broad range

adaptive immunity

Adaptive Immunity

– Specific antigen receptors

– B cells (humoral immunity)

– T cells (cell mediated immunity)

– NKT cells (cell mediated immunity)

fat microphage is going to turn on immune response

treg cells shut down immune response

innate immunity

every animal has this, first line of defense and conserved mechanism of host defense against infection

Distinguishes self from non-self perfectly

Defects in innate immunity are very rare and almost

always lethal

nonspecific defense

does not require specific antigen receptors or prior exposure/learning

provides barriers to prevent the spread of infection

identifies and eliminates pathogens and other foreign bodies

initiates an inflammatory response

activates specific immune responses

neutrophils

present in blood (60-70%) of WBC

present in tissues at relatively low levels, increase following injury or infection

short span 9-12 hours

functions:

• first cell at the site of infection/injury

• ingest and kill microbes and foreign materials; activation involves PAMPS and DAMPS binding to PRRs

need to be called in by the tissue resident macrophages (actual real responders)

mononuclear phagocytes

blood- monocytes (1-6%) WBC

tissues- macrophages

resident and inflammatory macrophages

resident macrophages

located throughout the body; largest populations in liver and lung most embryonic origin

inflammatory macrophages

respond to injury and infection, bone marrow derived

macrophage functions

identify and eliminate pathogens and other foreign materials

• non-specific recognition system, PPRS activated by PAMPS or DAMPS

regular inflammatory responses, promote angiogenesis, and initiate wound healing

maintain homeostasis, lipid, and iron metabolism

major secretory activity

activate adaptive immunity antigen processing and presentation

tumor surveillance and cytotoxicity

m1 macrophages

cytotoxic/ proinflammatory

produce ros, rns, il-12, tnfa, chemokines

m2 macrophages

anti inflammatory/ wound repair

produce il-10, tgfb, arg, vegf, egf

subsets m2a, m2b, m2c, m2d

macrophage activation

as environmental cues and regulators change in response to pathophys conditions, marcophages readily modify their phenotype (phenotypic switching)

mixed phenotype macrophages co exist w m1 and m2 macrophgaes

m1 to m2 reprogramming is key to the resolution of inflammation and wound repair

inflammation

dybamic response of a vascularized tissue to injury or infection

physiologic protective responses

serves to bring defense and healing mechanisms to the site of injury

fiunctions

neutralizes or destroy offending agent

restrict tissue damage to smallest possible area

alerts body and prepares injured tissue for repair and healing

acute inflammatory response

short term responses (typically lasts days)

initial response: proinflammatory/ cytotoxic

cellular response: proinflammatory neutrophils and m1 macrophages accumulate at injured site to release mediators to destroy pathogens and recruit additional inflam cells

secondary response anti inflammatory/ wound repair

cellular response: proresolution m2 macrophages accumulate and release mediators that suppress inflammation and promote wound repair

resolution of acute inflammation

neutrophils undergo apoptosis

resp;vong mediations released and stimulate m2 macrophage efferocytosis (act of macrophages phagocyting and removing dead neutrophils)

m2 macrophage release mediations that down regular inflammation and initian wound repair and angiogensis

inflammation fails to resolve

chronic inflammation- persistence of inflammatory neutrophils and macrophages, perpetuation of tissue injury, fibrosis/ scarring

foreign body response- frustrated phagocytosis, macrophages wall of injurious agent

granulomas

cancer

chemotaxis

migration to injured or infected site mediated by chemotactic factors

phagocytosis

ingestion of foreign substances, receptor mediated, active process, requries energy

metabolic destruction

intracellular digestion'; killing

oxygen independent: antimicrobial proteins, cationic proteins, lysozyme, acid hydrolases

oxygen dependent: myeloperoxidase, reactive oxygen species, reactive nitrogen species

foreign body reaction

if macrophages cant destroy the object they wall it off to protect the body

fusion of macrophages into giant cells along w other immune cells, formation of a fibrous capsule around the foreign body

outcome of fbr depends on size of foreign body, structure and surface characteristics

pathologic granulomas can form, usually smaller substaces, chronic inflammatory response

secretory functions of macrophages

2nd most potent secretory cell in body

enzymes capable of degrading extracellular matrix proteins

products involved in host degense

regulatory proteins

excessive release of mediatiors by overactive macrophages

can damage normal tissues

macrophage immune functions

antigen processing and presentation

tumor cytotoxicity

tumor surveillance

macrophage antigen processing

phagocytosis of antigen

partial degradation or unfolding

binding to mhc 2 proteins

re expression of processed antigen on cell surface with mhc 2

presentation to t helper cells

nk cells

type of cytotoxic lymphocyte

part of innate immune system

apoptosis mediated by small granules of perforin and granzyme

response is independent of mhs and antibodies= faster response < 3 days

innate lymphoid cells

derived from clp

part of innate immune system

no specific antigen recptor

regulate homeostasis and inflammation

humoral immunity

Mediated by B lymphocytes which produce

antibodies or immunoglobulins (Ig) in

response to antigen challenge

Five Classes: physical, chemical and

antigenic differences

antibodies

glycoproteins; selective, highly

specific; found in y-globulin fraction of

serum (humoral=blood)

igM

primary immune response (7%); Type III

hypersensitivity reaction; immune complexes;hypersensitivity reaction; immune complexes;

B cell receptorB cell receptor

pentamer

igG

secondary immune response, B memory

cells (70%)cells (70%

igA

external secretions, produced locally

against bacteria and viruses (15%)against bacteria and viruses (15%

monomeric, becomes multimeric in the endothelium and acquires a glycoprotein that proteins it against digestion

igE

Type I hypersensitivity reactions, minute

amountsamounts

igD

umbilical cord blood, primitive recognition

or regulation; B cell receptoror regulation; B cell receptor

antibody structure

Y-shaped, protein molecule that binds to a specific antigen to neutralize or mark it for destruction. It consists of two identical heavy chains and two identical light chains connected by disulfide bonds. top is variable region antigen binding site and bottom is cellular binding state

secondary immune response

igM and igG

– Shorter lag

– Higher levels of specific IgG produced

– Steady state level persists longer

– IgG predominates

– Quantitative difference between primary

secondary immune response due to an increase

the number of potentially reactive B cells

primary immune responses to antigen are

transient (passive)

b cells

will only recognize particular antigens to activate , will be making monoclonal antibodies, only one role

monoclonal antibodies

revolutionized immunology; involves development

of single antibody secreting immortalized cell

monoclonal antibodies benefit

monoclonal antibodies- no two antisera identical

reproducible- identical antibody more specifc and reliable

unlimited quantities- permanent cell line, grows indefinitely and produces very large amount

antigen need not to be pure or characterized

antigen

substance recognized as foreign

hapten: small molecule that binds to antibdoy does not elicit immune response

immunogen: foreign substance that binds antigen and elicts immune response

carrier: large protein

hapten + carrier= immunogen

t-independent antigens

– Complex carbohydrates

– Do not require processing

– Can directly interact with B cells

– No memory

t-dependent antigens

Require macrophages or other APC

– Require T-helper cells

– Require major histocompatibility antigens

– Mostly proteins

antibody-antigen interactions

not covalent, ionic, or perm binding

occurs in the variable region of the antibody molecule

cell mediated immunity

Mediated by t lymphocytes which release soluble mediators

important in host defense against viruses etc, transplant rejection and tumor surveillance

t cells

derived from precursor cells in bone marrow, mature in thymus, become educated

t cell education

learning to distinguish between self and non-self

controlled by mhc (self marker) proteins

specific for a given polypeptide chain to become activated

antigen recognition by t cells

specific t cell receptor

are MHC RESTRICTED- only recognize antigen together with major MHC protein

t helper cells recognize processed antigen and MHC II (self)

Cytotoxic TA cells recognize processed antigen and MHC I (non-self, altered self)

successful immune response also requires costimulatory and or coinhibitory molecules

immune checkpoints

MHC

large cluster of genes coding for proteins essential in regulation of immune cell function; destruction of non self

class 1 MHC

expressed on all somatic cells; classic “transplantation antigens”

class II MHC

Expressed on immune cells, immune associated antigens, important in immune regulation

class III MHC

complement

plasma proteins that play a role in lysing cells that are foreign or attractant compounds

not species specific