Immunity: Innate vs. Adaptive Defenses

Innate vs. Immunity

• Innate resistance is something an individual is born with.
• Immunity can be adaptive or innate, with adaptive immunity developing over time.

Lines of Defense

• First Line: Physical barriers like skin, mucous membranes, and hair, Chemical barriers like sweat, saliva, stomach acid, and Mucosal barriers like the respiratory and GI systems.
• Second Line: Includes proteins like the complement system, coagulation cascade, and Bradykinin (kinin system), as well as cells like neutrophils, monocytes, basophils, and eosinophils.
• Third Line: Adaptive immunity involving T and B cells accumulated over time, has specific responses.

Inflammation

• Inflammation is a sudden, non-specific response to stimuli disrupting homeostasis.
• Acquired immunity develops over time and uses specific T and B cells to fight disease.

Microscopic Inflammation

• Microscopic findings include mast cell degranulation, activation of plasma system, and release of cellular products.
• Macroscopic findings include vasodilation (heat and redness), vascular permeability (edema), cellular infiltration (pus), thrombosis (clot), and stimulation of nerve endings (pain).

Acute Inflammation

• Local signs of acute inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain).

Plasma protein systems

• Complement System: alternative pathway through C3b binds to bacterial wall, has chemotaxis factor of C3b + C5a ramp up inflammation form C3a and C5a.
• Coagulation System: forms clot and walls off pathogens (fibrinopeptides).
• Kinin System: bradykinin increases vasodilation, increases permeability, and causes pain.

Primary Cells of Inflammation

• Monocytes: still in circulation.
• Macrophages: more intense and active.
• Neutrophils: first to be activated, aggressive.
• Eosinophils: fight parasites and regulate histamine.
• Basophils: mast cells in circulation.
• Platelets: form a plug and fibrinogen clot.
• Lymphocytes: B and T cells of adaptive immunity.

Pattern Recognition Receptors

• PRRs bridge innate and adaptive immunity.
• PAMPS include DNA, RNA, and lipoproteins like lipopolysaccharide (LPS) on bacterial membranes.
• DAMPS include mitochondrial DNA and high mobility group box-1 (HMGB-1).
• Toll-Like Receptors recognize PAMPS on a large group of organisms.

Mast Cell Degranulation

• Caused by PAMPS like bacteria and viruses.
• Also caused by DAMPS (injury), antibody/IgE-mediated mechanisms, C3a+C5a (anaphylatoxin), and Interleukin-1 (increasing inflammation).

Histamine Effects

• H1 receptors in primary inflammatory cells (especially epithelial) use second messengers to contract smooth muscle, a concentration-dependent effect.
• H2 receptors are anti-inflammatory, blocking histamine and regulating stomach acid.

Mast Cell Synthetic Products

• Leukotrienes cause exudation and produce cytokines, IL-13, and growth factors like VEGF and PDGF for healing.
• Prostaglandins produce pain and increase TNF-a.

Inflammatory Process

• Neutrophils act as phagocytes with NADPH oxidase and undergo NETosis.
• Macrophages also act as phagocytes but have limited NADPH oxidase.

Phagocytosis

• NADPH oxidase gives electrons to oxidase, creating super oxidase (heme based).
• NETosis involves neutrophils lysing themselves and ejecting nucleus DNA + Histones trapped in NET.
• Phagocyte migration: phagocytes move from bloodstream into tissues to fight infection.

Cytokines

• Lymphokines signal and activate immune cells to migrate, enhance activity, destroy pathogens, and regulate overall immune response.
• Interferons stimulate healthy cells to produce substances preventing viral infections.
• Interleukins activate growth and differentiation of leukocytes; contribute to systemic inflammatory changes like fever.
• Nuclear Factor-kappaB (NF-kB) has multiple pro-inflammatory effects: vascular effects, chemotaxis, cellular proliferation, systemic inflammatory changes.

Systemic Signs of Acute Inflammation

• Fever: increases enzymatic activity and cellular activity.
• Leukocytosis: increase in white blood cells (“buffy coat”).
• Plasma Protein Synthesis: production of pro-inflammatory or anti-inflammatory proteins (acute-phase reactants).

Chronic vs. Acute Inflammation

• Chronic inflammation lasts more than 10 days, potentially weeks, months, or years.
• Acute inflammation lasts 7-10 days and can heal, returning to homeostasis.

Granuloma Formation

• Fusion of macrophages forms multi-nucleated cells around pathogens.
• A giant mass of cells continues cytokine release.
• Granuloma: pathogen in middle, T+B cells around with giant cells; fibrous coat forms due to coagulation cascade.

Tissue Resolution

• Tissue Resolution: returns tissue to homeostasis (fixes and goes back to normal).
• Tissue Repair: holds tissue integrity but loses function, resulting in SCAR formation.

Immunogens

• Immunogens stimulate an immune response to pathogens, noninfectious environmental agents, drugs, vaccines, transfusions, and transplants.

Antigen-presenting cells

• APCs recognize invaders/foreign tissues, then process and present the antigen to lymphocytes.
• Macrophages, dendritic cells, and B cells serve as APCs.
• Macrophages: Phagocytes derived from circulating monocytes reside in tissues, especially near epithelial surfaces (detect both PAMPS and DAMPS).
• Dendritic Cells: Specialized type of macrophage conventional, follicular, plasmacytoid.

Histocompatibility complex

• MHC I: expressed on all nucleated cells, present normal self antigens
• MHC II: on antigen presenting cells (macrophage, B cells, dendritic cells)

Cellular Immunity vs. Humoral Immunity

• Cellular Immunity: defends against intracellular pathogens (viruses) and abnormal cells (cancer cells); leaves behind memory T-Cells from apoptosis through releasing granzymes and perforins
• Humoral Immunity: defends against extracellular antigens; releases one kind of antibody.

Active vs. Passive Immunity

• Active Immunity: acquired through infection (natural) or vaccination (artificial).
• Passive Immunity: given without developing, such as maternal antibodies (natural) or monoclonal antibodies (artificial).

Immunogenicity

• An antigen that can trigger an immune response
  • Degree of foreignness to a host

Antigenic Determinant

Paratope: the receptor we develop in response to pathogen Epitote: Antigenic Determinant

Self Tolerance

• A recognition of self as not foreign.

Central and Peripheral Tolerance

• Central: lymphocytes with receptors against self-antigens are eliminated (proof read) make sure we don't make cells that will attack itself
• Peripheral: prevents recognition by lymphocytes and antibodies

B Cell in Humoral Immunity

• B Cell: B cell will develop through helper T cell and cytokine activity. Will then become a plasma cell and go through apoptosis and develop one type of antibody.

T Cell in Cell-Mediated Immunity

• T Cell: Produces chases in characteristic surface markers – initiates the expression of CD2 on the cell surface (memory cells), developing T cells make surface proteins CD4 and CD8.
  • CD4: recognize antigens presented by MHC II molecules and develop into T-helper cells
  • CD8: recognize antigens presented by MHC class I molecules and develop into cytotoxic T-cells

Immunoglobulins (Antibodies)

• IgG: most protective against infection, crosses placenta, most prevalent.
• IgA: most protective activity in body secretions (tears, saliva, mucous).
• IgE: mediates allergic responses, defends against parasitic infections (most rare).
• IgM: first antibody produced during initial/primary response, largest.
• IgD: Functions as one type of B-Cell antigen receptor – NOT WELL KNOWN

Antibody Structural Components

• Antigen Binding Fragment (Fab): Binds antigen, amino acid sequence of the variable regions of the heavy and light chains.
• Crystalline Fragment (Fc): Activates complement system and opsonization.

Actions of APC

• APCS: Th Cells: help inflammatory response
  • Th1: provide help in developing cell-mediated immunity activate macrophages and Tc Cells
  • Th2: provide help in developing humoral immunity activate B cells
• Tc Cells (secondary exposure): binds antigen to T-cell receptors (memory cells) directs killing of foreign/ abnormal cells (Tc cells or cytotoxic T lymphocytes [CTLS]) assistance or activation of other inflammatory and T-Cells
• Treg Cells regulate the immune response to avoid attacking “self”, limit immune response – bind cytokines

Immune Response Stages

• Primary immune response: initial exposure to A, activation of Tc, short lived plasma cells,
• Upon secondary exposure to A does secondary immune response kick in
• Secondary response: memory B cells + memory T cells memory B cells differentiate into plasma cells long lived plasma cells in bone marrow memory B cells ANTIBODIES TO A

Titer

• Titer, amount of antibodies in a serum sample, a higher titer indicates more antibodies that are interchangeable with immunoglobulins.
  • Upon the secondary response is the result of memory cells that are already differentiated
  • IgM may be produced in the secondary response
  • IgG production is increase – making is the predominant antibody class.
  • Natural infection may result in measurable levels of protective IgG for the individual's life.

Protection Against Infection

• Antibodies can be done directly (through action of antibody alone) can providing protection against infections by Neutralization (inactivating or blocking the binding of antigens to receptors). Also through agglutination or precipitation (clumping insoluble particles in suspension).

Opsonization

• Helps the immune system identify and destroy pathogens

Secretory Immune System

• Protects the external surfaces of the body through lacrimal & salivary glands and a network of lymphoid tissues residing in the breasts, bronchi, intestines, and genitourinary tract. Plasma cells in these sites secrete antibodies in bodily secretions to prevent pathogenic microorganisms from infection and penetrating the body's surfaces.

Hypersensitivity

• A condition characterized by an excessive or misdirected adaptive immune response.
  • Original “insult”: alters immunologic homeostasis
  • Individual's genetic makeup: determines the degree of the resultant immune response from the effects of the insult no gene but familiar makeup
  • Immunologic Process: causes disease symptoms – manifestation of disease can be through inflammation

Abnormal Immunity

• Allergy: An exaggerated response against an environmental antigen.
• Autoimmunity: A misdirected response against the host's own cell.
• Alloimmunity: directed against beneficial foreign tissues (transfusions, transplants)

Hypersensitivities

• Type I: IgE mediated, against environmental antigens, IgE binds to crystalline fragment receptors on surface of MAST CELLS; cross linking causes the release of histamine through: H1 and H2 receptors that Increase chemotactic activity and is associated with anaphylaxis.
• Type II: tissue specific responses where a specific cell or tissue (tissue-specific antigens) is the target of an immune response that happens through five mechanisms:
  • Cell is destroyed by antibodies and complement
  • Cell Destruction occurs through phagocytosis
  • Neutrophils release granules – ROS, acid environment
  • Antibody-dependent cell -mediated cytotoxicity is present
  • Causes target cell malfunction Ex: blood transfusion reaction
• Type III:is immune (antigen-antibody) complex mediated complexes are formed in circulation and deposited later in vessel walls or extravascular tissues that are NOT organ specific & Damage results from complement activation: Immune Complex clearance
• Large: macrophages
• Small: renal clearance
• Intermediate: deposited in tissues; causes problems
• Type IV: mediated by T lymphocytes or is cell mediateddestruction of the tissue is usually cause by direct killing by toxins from cytotoxic T (Tc) cells. Where Helper T (Th) 1 and Th 17 cells produce cytokines that recruit phagocytes, especially macrophages :

Desensitization

• Reduces the severity of an allergic reaction in treated individual by prolonged exposure to previously sequestered antigen.
• Molecular mimicry: viral infection – immune system recognize own protein that look like viral new protein
• Development of a neoantigen & - ineffective peripheral tolerance

Alloimmunity Rejection

Characterized by :

• Neonatal alloimmunity: fetus has antigen – mother doesn't Fetal platelets carrying antigen enter maternal circulation develops antibodies & Alloreactive effector T-cell will attack graft Characterized by deterioration or complete loss of graft function

Graft Rejection

• Hyperacute: immediate and rare – occurs because of the presence of preexisting antibodies (type II hypersensitivity) to HLA antigens on the vascular endothelial cells in the grafted tissue
• Acute: occurs within days to months after transplantation recipient develops an immune response against unmatched HLA antigens
• Chronic: occurs after months/years, characterized by slow, progressive organ failure, happens if poorly matched to their donor, have comorbidities transplant procedures, requires treatment for multiple acute rejection episodes

Cognitive Arousals

• Arousal is an individual's Alertness where a Consciousness and awareness is the ability to perceive and response to stimuli that work together to experience the world around us

Alterations causes

• Structural Alterations:
  • Head trauma, stroke, tumors
  • RAS & brain stems reflexes
• Metabolic Alterations:
  • disruption of chemical balance(Hypoxia)
• Psychogenic: disruption in Mental-Emotional function
  • Poor sleep habits

Levels of Consciousness

• Confusion: slow thinking, impaired judgement
• Lethargy: limited spontaneous activity, don't have enough energy to respond to environment
• Obtundation: mild reduction in arousal, may drift to unconsciousness
• Stupor: involved very intense physical stimulus, deeper reduction in arousal, more unresponsive
• Coma: no response, limited motor reflexes

Clinical Manifestations

• Oculocephalic Reflex response: eye movement, can cause damages to the brain stems

Abnormal Injury

• Lesions characterized in:
  • Cheyne-Stokes: metabolic injury
  • Central Neurogenic hyperventilation: metabolic encephalopathies (lesion often caused by mid- brain death)
  • Pontine lesions: Breathing characterized by rapid inhalation, pause, exhale, and apnea (apneusis)
  • Ataxic Breathing: occurs when the medullary ventral respiratory nuclei are injured -mismatched signals, loss of pattern
• Entire brain (brain stem) stops functioning
  • Cerebral death maintains homeostasis

Brain clinical signs

• Coma: response to an acute brain injury
  • Chronic Coma: doesn’t respond & Vegetative State: above coma
• All Based around: Neurons will not be a straight line, patients can be stuck/ heal for as long as they can
  • Minimally conscious: recovery may come
  • Locked clinical motor cognitive: No recovery
• Hemiplegia (paralysis or Weakness on one side of the body) all based around Neurons

Seizures

• Provoked Seizures caused by injuries (head trauma, stroke, Alzheimer's
• Unprovoked Seizures caused by an epileptic syndrome with explosive discharges

Seizures Signs

• Aura: warning signs, patients will experience hallucinations (confusion that leads to prodroma)
• Prodroma: Inability to interact from environments sending patients into ionic stage
• Tonic Stage: patients experience full body contraction
• Chronic state: Patients experience a jerky movement causing frothy saliva (Postictal State)

Status epilepticus

• Status epilepticus: continuing or recurring seizures
• Status Epilepticus caused by a Chronic medical condition caused by 2 or more seizures

Memory

• Anterograde: trouble making memories following injury
• Retrograde: remembers

Processing Disorders

• Agnosia: Inability to recognize injuries
• Dysphasia (Aphasia): a general term to describe a language disorder relating to brain activities

Alzheimer

Neurofibular tangles+ Proteins plaques cause symptoms like troubled memories with inability to recognize, with emotional & physical instability

Brain Proteins

The protein accumulation the disease

• Tau Protein: results in increase cytoskeleton proteins

Stages of Intracranial

Brain stage related with Alzheimer All start with-Normal brain

• (50%) with increased blood flow (23%)
• Suffering brain(45%) slow bleeding flow
• Dying thresholds (35%)
• Death Rate (10%)
• Symptoms are 2/3 of Alzheimer

Cerebal Edema Causes

Trauma injuries with tumor are infections Failure of the infection is the loss of process

• Cytotoxic/Schemic & Hemoplia
• Motor Neuron=LSL (dies sending gasps of neurons will be 3/5 per years.) Neuromodulators: ULN loseness member potential (no information)

Hemiplegia

• (Hereditary), medical condition
• Diplegia conditions (symmetrical)
• Paraplegia impairs/snesory Quadriplegia are 4 links. (Motor/neurons)