Unit 2

Immunity

to protect our body from injury and infection; the body’s ability to defend against specific pathogens and/or foreign substances responsible for the development of disease

Dendritic cells

component of both innate and adaptive immunity by acting as a communication link (release cytokines and chemokines)

Cytokines and chemokines

• signaling/communication molecules

• IL-1—12, Type I interferons, Interferon-gamma, Tumor necrosis factor-alpha, chemokines, granulocyte-monocyte CSF, granulocyte CSF, and monocyte CSF

Interleukins (ILs)

• Produced by macrophages and lymphocytes

• Enhance the acquired immune response or regulate, through suppression or enhancement, the inflammatory process

Interferons (IFNs)

Cytokines that protect the host from viral infections and help modulate the inflammatory response

TNF-alpha

• Cytokine that mediates the inflammatory response and is present in inflammation, cancer, autoimmunity, and infection

• Endogenous pyrogen

Innate immunity

• Non-specific defense mechanisms

• Timeline: 0-12 hours

• Uses PRRs to recognize specific surface structures

• 1st line of defense: skin, mucous membranes, secretions of the skin, secretions of the mucous membranes

• 2nd line of defense: inflammation

Inflammation

• Capillary widening to increase blood flow

• Increased permeability leads to fluid release into the tissues

• Attraction of leukocytes leads to extravasation of leukocytes to the site of injury

• Systemic response leads to fever and proliferation of leukocytes

• The reaction of vascularized tissues to injury

• Characterized by inflammatory mediators

Acute inflammation

• Short duration; exudation of fluid and plasma components and emigration of leukocytes into the extravascular tissue

• Protective process of local tissues and blood vessels to heal the injury

• Two phases: vascular phase and cellular phase

Vascular phase of inflammation

• Increase in blood flow and changes in the small blood vessels of the microcirculation

• Vasodilation and vascular permeability

Cellular phase of inflammation

• Migration of leukocytes from the circulation and their activation to eliminate the injurious agent

• Polymorphonuclear neutrophils (PMNs) – delivered to the site of injury

• Margination and adhesion to the endothelium – leukocyte accumulation

• Transmigration across the endothelium

• Chemotaxis – directed cell migration

• Activation and phagocytosis

• Three steps: recognition and adherence, engulfment, and intracellular killing

Inflammatory mediators

• Vasoactive and smooth muscle-constricting properties

• Plasma proteases that activate members of the complement system, coagulation factors of the clotting cascade, and vasoactive peptides of the kinin system

• Chemotactic factors

• Reactive molecules and cytokines liberated from leukocytes

Local manifestations of inflammation

• Serous exudates – watery fluids low in protein content

• Hemorrhagic exudates – where there is severe tissue injury that damages blood vessels

• Fibrinous exudates – large amounts of fibrinogen

• Pseudomembranous exudates – on mucous membrane surfaces and made up of necrotic cells

Chronic inflammation

• longer duration; presence of lymphocytes and macrophages, proliferation of blood vessels, fibrosis, and tissue necrosis

• Self-perpetuating

• Infiltration by mononuclear cells and lymphocytes

• Proliferation of fibroblasts instead of exudates

• Nonspecific chronic inflammation – diffuse accumulation of macrophages and lymphocytes at the site of injury

• Lymphadenitis – infection in one or more lymph nodes

Characteristics of the 2nd line of defense

• Nonspecific and rapid

• Caused by a variety of materials – infection, tissue necrosis, trauma, injury, foreign bodies, immune reaction, ischemia, etc.

• Macrophages, other phagocytes (ex., neutrophils, NK cells), antimicrobial proteins, inflammatory response (ex., redness, fever)

Cells involved in the 2nd line of defense

• Neutrophils – phagocytic cells

• Monocytes – released from the bone marrow into the bloodstream → become macrophages that phagocytize foreign substances

• NK cells – spontaneously kill target organisms

5 cardinal signs

redness, heat, swelling, pain, and loss of function

PAMPS

structures on the cell membranes of invading pathogens that are recognized by the innate immune system by PRRs

Adaptive immunity

• Specific defense mechanisms; acquired through previous exposure to infections and other foreign agents; able to recognize and destroy specific foreign agents

• Timeline: 1-7 days

• 3^rd line of defense

• Antigens (antibody generators)

• B and T-lymphocytes

• Antibodies (B cells → plasma cells)

3rd line of defense

• Lymphocytes (B & T Cells, antigen-specific, antibodies, memory

• Humoral immunity, cell-mediated immunity, and the complement system

Humoral immunity

• Mediated by B lymphocytes

• Defense against extracellular microbes and their toxins

• B cells differentiate into plasma cells → interact with and destroy microbes → become memory cells

Cell-mediated immunity

• Mediated by T lymphocytes

• T lymphocytes arise in the bone marrow and mature in the thymus  → CD4+ and CD8+

• Helper T cells – secrete cytokines → can activate and regulate B cells, cytotoxic T cells, NK cells, macrophages…

• Cytotoxic T cells – monitor the activity of all body cells and destroy any that threaten the body’s integrity by recognizing antigens

• Elimination of intracellular pathogens

Complement system

• Process involving the sequential breakdown of complement proteins to generate a cascade of cleavage products capable of proteolytic enzyme activity

• Three pathways: alternative, classical, and lectin

• Initial activation phase

• Early-step inflammatory responses – activation of C3 → cleavage into a larger C3b fragment and C3a fragment → attracts neutrophils → opsonin for phagocytosis → C5a – vasodilation and increases vascular permeability and C5b – leads to late-step membrane attack responses

• Late-step membrane attack responses – formation of a complex of complement proteins C6—C9 → cell lysis

Active immunity

• When the host mounts an immune response to an antigen through vaccination or environmental exposure

• Involves development of memory

• Long-lasting

Passive immunity

• Immunity transferred from another source such as from a birthing parent to their fetus (IgG antibodies)

• Short-term protection

Endotoxins

• from gram-negative bacteria

• Don’t contain protein and aren’t actively released from the bacterium during growth

• No enzymatic activity

• Ex. E. coli, Neisseria meningitidis

Exotoxins

• Proteins released from the bacterial cell that may damage cells

• Neurotoxins, enterotoxins, cytotoxins

• Ex. Clostridium botulinum, Clostridium tetani

Disease course

• Incubation period

• Prodromal stage

• Acute stage

• Convalescent stage

• Resolution stage

Incubation period

Pathogen begins active replication without producing symptoms

Prodromal stage

Initial appearance of symptoms

Acute stage

The host experiences the maximum impact of the infectious process

Convalescent stage

Containment of infection, progressive elimination of the pathogen, repair of damaged tissue, and resolution of associated symptoms

Resolution stage

Total elimination of a pathogen

Redness (rubor)

• Blood vessel dilation

• Increased RBC concentration

Pain (dolor)

Stimulation of nerve endings

Heat (calor)

Increased blood flow and RBC concentration

Swelling (tumor)

• Increased permeability of blood vessels

• Exudate → movement of plasma proteins out of the capillaries

Sepsis continuum

• Increased permeability of blood vessels

• Exudate → movement of plasma proteins out of the capillaries

Systemic inflammatory response syndrome (SIRS)

• No longer localized

• Two or more of the following symptoms:

  • Temp > 38’C or <36’C

  • Heart rate > 90 bpm

  • Respiratory rate > 20 or PaCO2 < 32 mm Hg

  • WBC > 12,000/mm3, < 4,000/mm3, or > 10% bands

Sepsis

• Pathogen enters

• Dysregulated immune response

• Inflammatory response + toxins

Risk factors of sepsis

• Bacteremia

• Hospital/ICU admission

• Immune system deficiencies

• Recent surgery/hospitalization

• Indwelling medical devices

• Infants and older adults – weakened immune system

• Chronic disease

• Genetic factors

Complications of sepsis

• Septic shock – no longer responding to treatment

• DIC

• Multi-organ dysfunction syndrome

• Death

General/systemic presentation of sepsis

Fever, tachycardia, hypotension, hypoxemia, oliguria (decreased urine ouput), edema

Laboratory results of sepsis

• Increased WBC count, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)

• Indications of organ hypoperfusion, injury, and dysfunction

  • Increased serum lactate (generalized), glucose (stress response), creatinine (acute kidney damage), and bilirubin (liver damage)

• Impaired coagulation

  • Increased internationalized normalized ratio (INR), partial thromboplastin time (PTT), and platelet count (depending on timing)

• Blood cultures +

Antigens

• Antibody generators

• Substances foreign to the host that stimulate an immune response and are recognized by receptors

• Unique to each pathogen

• Reason for specificity seen in adaptive immune response

B and T lymphocytes

Specificity, diversity, memory, self-nonself recognition

Antibodies

• IgG – secondary

• IgA

• IgM – primary

• IgE – allergies

• IgD

Hypersensitivity

An abnormal or excessive response of the activated immune system that causes injury and damage to host tissues

Type I hypersensitivity reaction

• Immediate – classic allergic response

• Overactivation of IgE-mediated mast cell degranulation → releases prostaglandins and histamine

• IgE (high affinity for mast cells) and mast cells (located in GI tract, skin, and respiratory system)

• Must first have a sensitizing episode

• Basophils and eosinophils

• Histamine most potent — reacts within 15-30 minutes → bronchoconstriction, vasodilation, and increased vascular permeability

• Leukotrienes, PaF, prostaglandins

  • 2-24 hours

  • Late reaction that triggers other immune responses

Anaphylaxis

• Part of the type I hypersensitivity reaction

• Rapid and severe allergic reaction

• Life-threatening due to airway swelling and severe hypotension

Clinical manifestations of Type I Hypersensitivity reactions

Hypotension, dysrhythmias, bronchospasm, angioedema, itching

Type II Hypersensitivity reaction

• Overactivation of humoral antibodies (antibody-mediated disorders)

• Antibody-mediated and tissue-specific responses — mediated by IgG or IgM

• Self-reactive B cells bind antigens on host cells → antigen-antibody complex at the tissue (tissue- or cell-specific)

• Signs and symptoms depend on cells/tissues

Causes of Type II Hypersensitivity reactions

• Mismatched blood transfusions

• Hemolytic disease of the newborn

Transfusion reaction

• alloimmune reaction – attack something foreign to the body

• Have antibodies to the missing blood type

• Recipient antibodies bind to donor blood RBCs → agglutination

Clinical manifestations of transfusion reactions

• Temp change greater than 1.8’F

• Tachycardia

• Palpitations

• Hypotension

Type III Hypersensitivity reaction

• Overactive antigen-antibody binding w/overactive complement activity

• Antibody-mediated complex circulates and settles in the tissue

• Immune complexes and complement activation → complexes form in the circulation and settle into the vessel wall or tissue

• NOT tissue specific

• Diagnosis through antibody testing

Examples of Type III Hypersensitivity reactions

• Post-streptococcal glomerulonephritis

• Systemic lupus erythematosus

• Rheumatoid arthritis

Systemic lupus erythematosus (SLE)

• Chronic inflammatory disease

• Formation of autoantibodies and immune complexes → B-cell hyperreactivity and increased production of antibodies against self and non-self antigens

• Glomerulonephritis – formation of immune complexes within the glomerular capillary wall damages the glomerulus

Clinical manifestations of SLE

• Arthralgias, arthritis

• Flexion contractures

• Hyperextension of the interphalangeal joints

• Subluxation of the carpometacarpal joints

• Butterfly rash

• Hair loss

• Mucous membrane lesions

• Pericarditis

Clinical manifestations of Type III Hypersensitivity reactions

• Fever, fatigue, weight loss

• Skin – rash

• Kidney – proteinuria

• Joints – arthralgias

• Mucosa – ulcers

Type IV Hypersensitivity reaction

• Delayed

• Overactivation of T-cell-mediated immune response

• Direct cell-mediated (cytotoxic T cells (CD8+) or Th cells (CD4+)

• No antibodies

Causes of Type IV Hypersensitivity reactions

• Contact sensitivity to poison ivy

• Contact latex allergy

• Graft vs. host disease

Signs and symptoms of Type IV Hypersensitivity reaction

• Local inflammatory reaction

• Organ-specific cell destruction

• Chronic inflammation → organ failure

AIDS

Disease caused by HIV and is characterized by immunosuppression with associated opportunistic infections, malignancies, wasting, and CNS degeneration

HIV

• Retrovirus that attacks CD4+ T lymphocytes

• Three stages

  • Acute infection – rash, fever, fatigue, sore throat, night sweats…

  • Chronic asymptomatic/latency – 10 years or longer

  • Overt AIDS – CD4+ cell count less than 200 cells/μL

Diagnosis of AIDS

• HIV antibody test – enzyme immunoassay (ELISA) and Western blot assay

• Polymerase chain reaction (PCR) – detects HIV DNA

Three stages of wound healing

• Inflammatory phase

• Proliferative phase

• Wound contraction and remodeling phase

Inflammatory phase

• first phase of wound healing

• Formation of a blood clot and migration of phagocytic WBCs into the wound site

Proliferative phase

• Second phase of wound healing

• Fibroblasts secrete collagen, proteoglycans, glycoproteins, and growth factors (angiogenesis)

• Epithelialization – epithelial cells at the wound edges proliferate to form a new surface layer

Wound contraction and remodeling phase

• Third phase of wound healing

• Development of fibrous scar

Primary intention

sutured surgical incision

Secondary intention

• Larger wounds with a greater loss of tissue and contamination

• Slower and results in large amounts of scar tissue

Factors that influence healing

• Malnutrition – protein deficiency prolongs the inflammatory phase and impairs fibroblast proliferation, collagen, and protein matrix synthesis, angiogenesis, and wound remodeling; missing necessary vitamins and minerals

• Inadequate blood flow and oxygen delivery

• Impaired inflammatory and immune responses – disorders, DM, corticosteroid drugs

• Infection, wound separation, and foreign bodies

  • Infection prolongs the inflammatory phase, impairs the formation of granulation tissue, and inhibits proliferation of fibroblasts and deposition of collagen fibers

• Bite wounds – infection

Allostasis

The physiologic changes in the neuroendocrine, autonomic, and immune systems in response to challenges to homeostasis

Allostatic overload

Cumulative effects of chronic stress; cortisol and stress hormones lead to negative effects on the body systems and can lead to inflammation, HTN, hyperglycemia, and other health risks

Stress response

• Alarm stage

• Resistance stage

• Exhaustion stage

Alarm stage

Generalized stimulation of the sympathetic nervous system and HPA axis → release of catecholamines and cortisol

Resistance stage

• Increased cortisol levels drop

• The body selects defense

Exhaustion stage

When resources are depleted, and signs of “wear and tear” or systemic damage appear

Role of cortisol

• Maintains blood glucose levels by antagonizing insulin and enhances the effect of catecholamines

• Suppresses osteoblast activity, hematopoiesis, collagen synthesis, and immune responses

• Suppresses growth hormone

Mutation

change in DNA that is present in <1% of the population

Single-nucleotide polymorphism (SNP)

change in a single base pair seen in >1% of the population

Copy number variation (CNV)

large sections of DNA, from thousands to millions of base pairs, that have been copied

Epigenetics

chemical additions that affect gene expression

De novo genetic mutations

• New mutations that arise spontaneously and are not inherited

• Occurs in DNA during cell division, sperm or egg formation, or early embryonic development

Induced genetic mutations

• Mutations caused by exposure to external mutagens or damaging agents

• DNA is damaged by a mutagen → if the damage is not repaired correctly, a mutation can occur when the cell divides

Germline mutations

Occur in reproductive cells before fertilization and can be passed to offspring

Somatic mutations

Occur in non-reproductive (body) cells and cannot be passed to future generations

Missense mutation

single nucleic acid change that results in the coding of a different amino acid

Nonsense mutation

A premature coding of a stop codon that ends translation early, resulting in an incomplete protein

Frameshift mutation

when one nucleic acid is inserted or deleted, the entire strand is shifted

Deletion mutation

when one or more nucleotides are lost during replication

Insertion mutation

When one or more nucleotide bases are inserted into a DNA sequence

Duplication mutation

a type of genetic change when an extra copy of a part of a DNA sequence or a whole chromosome is produced

Autosomal recessive

• Two copies of the mutated gene are required to show the trait

• Ex. cystic fibrosis, sickle cell, albinism…

Autosomal dominant

• One copy is enough to show a trait

• Penetrance – whether someone will develop a condition or not; proportion of individuals with a genetic variant who actually express the phenotype

• Expressivity – the degree or severity of the phenotype among individuals who express the trait; can vary widely even within the same family

• Ex. Huntington disease, achondroplasia, osteogenesis imperfecta…

X-linked recessive

• The mutated gene is on the X chromosome

• Males with one mutated copy will be affected

• Ex. hemophilia A& B, Duchenne muscular dystrophy (DMD), Rett syndrome…

X-linked dominant

• A single mutated gene on the X chromosome (lowercase x) is enough to cause the trait

• Ex. Hypophosphatemic rickets, Alport syndrome, incontinentia pigmenti…

Mendelian/monogenic inheritance

• autosomal recessive

• autosomal dominant

• X-linked recessive

• X-linked dominant

Non-mendelian inheritance

• mitochondrial

• mosaicism

• genetic imprinting

• uniparental disomy