Advanced Patho Week 2: Infection, Immunity and Inflammation

Inflammation:
 Characterized by inflammatory mediators, neutrophils and the movement of fluid
 Localize and eliminate microbes and foreign particles
 Allows for repair of injured tissue
 Cellulitis
o Inflammatory condition
 Superficial infection of the skin
 Suffix = itis
o Added to affected organ; appendicitis, pericarditis
 Causes
o Immune response to infectious microorganisms, trauma, surgery, caustic chemicals, extreme heat/cold,
ischemic damage to body tissues
 Degree of inflammatory response depends on the stimulus
o Minor sunburn, short fall and foot injury compared to compound fracture or more severe trauma
 Dependent upon:
o Length of time of the attack by the infectious agent
o Type of infectious organism
o Degree of injury
o How well is the person able to fight off the organism (microenvironment)
 Cardinal Signs of Inflammation
o Rubor (redness)
o Tumor (swelling)
o Calor (heat)
o Dolor (pain)
o Functio laesa (loss of function)
 Fever is SYSTEMIC manifestation due to chemical mediators/cytokines.

Acute Inflammation
o Short duration; nonspecific early response due to injury
o Aimed at removing the injurious/infectious agent and liming tissue damage
o Involves the infiltration of neutrophils
o Exudate often present (drainage)
o Vascular Stage
 Increase in blood flow
 Momentary vasoconstriction then rapid dilation of the blood vessels of the microcirculation
 Manifestations: swelling, redness
o Cellular Stage
 Evidenced by migration of leukocytes and the elimination of the infectious or irritating agent
o Primary function of inflammatory response  limit the damage from the infectious/pathologic agent,
remove the injured tissue, and allow tissue repair/healing to occur.
 Vascular Changes with Inflammation
o Vasoconstriction (brief)
o Vasodilation  redness
o Increased vascular permeability
o Leakage of exudate (protein-rich fluid) into tissues causing edema
o Fluid movement out of the vessel causes stagnation of flow and clotting of blood which helps to localize
infection.
o Follows one of three patterns of response:
 An immediate transient response
 Occurs with minor injury (typically affects venules)
 An immediate sustained response
 Occurs with more serious injury and continues for several days (affects arterioles,
capillaries and venules)
 Delayed hemodynamic response
 Often due to radiation; sunburn
 Involves delayed endothelial cell damage leading to an increase in capillary permeability
that occurs 4 to 24 hours after injury
 Cellular Stage of Acute Inflammation
o Due to changes in the endothelial cells lining the vasculature and the release of chemical mediators from
mast cells and macrophages
o Cellular changes cause the movement of phagocytic leukocytes into the area of injury/infection
o Leukocytes that participate in the inflammatory response include:
 Granulocytes  neutrophils, eosinophils, and basophils
 Monocytes  the largest of the white blood cells
 Cellular Response to Inflammation
o Margination and adhesion to the endothelium
 Leukocytes concentrate along the vessel wall and accumulate (margination)
o Transmigration across the endothelium
 Leukocytes then transmigrate through the vessel wall
o Chemotaxis
 Directed cell migration via chemokines (small proteins that direct the trafficking of leukocytes)
o Leukocytes activation and phagocytosis
 Final stage of the cellular response
 Monocytes, neutrophils & macrophages engulf and breakdown cellular debris through
phagocytosis
Inflammatory Mediators  originate from cells or plasma

 Histamine
 One of the first mediators released
 Causes dilation and increased permeability of veins
 Cytokines
 Control cell immune response
 Important in acute and chronic inflammation
 Arachidonic acid Metabolites
 Prostaglandins and leukotrienes
o NSAIDs inactivate the first enzyme for prostaglandin synthesis
o Omega 3’s stop production of inflammatory mediator
 Platelet-activating factor
 Induces platelet aggregation
 Plasma Proteins
 3 related systems: clotting, complement and kinin systems
 Clotting contributes to vascular phase
 Complement proteins ↑ vascular permeability, phagocytosis and vasodilation
 Kinin system is short; causes ↑ vascular permeability, contraction of smooth muscle and
dilation of vessels
Inflammatory Exudates
 Serous Exudate
 Watery fluids low in protein content
 Result of plasm entering the inflammatory site
 Hemorrhagic Exudates
 Occur when there is severe tissue injury that causes damage to blood vessels or when there is
significant leakage of red cells from capillaries
 Membranous or Pseudomembranous Exudates
 Develop on mucous membrane surfaces
 Composed of necrotic cells enmeshed in a fibro-purulent exudate
 Purulent or Suppurative Exudates
 Contain pus; composed of degraded white blood cells, proteins and tissue debris
 Fibrinous Exudates
 Contain large amounts of fibrinogen and form a thick and sticky meshwork

Chronic Inflammation
o Longer duration, self-perpetuation and may last days, weeks, months or years
o Can be due to a recurrent or progressive acute inflammatory process or a low-grade smoldering response that fails
to evoke an acute response
o Infiltration by macrophages and lymphocytes not neutrophils
o Neutrophils are involved in acute inflammation
o Proliferation of fibroblasts not exudates
o Causes:
o TB, syphilis, foreign bodies, surgical material in the body

Systemic Manifestations of Inflammation

  Acute Phase Response (hours or days)
o Changes in the concentration of plasma proteins, ↑skeletal muscle breakdown, negative nitrogen balance,
elevated ESR and ↑ leukocytes
 Manifestations: Fever, anorexia, fatigue and malaise
 Neutrophils are released from bone marrow, they have a lifespan of 10 hours and must be replaced to maintain an
adequate response to infection
o Excessive demand leads to immature forms of neutrophils (bands)
o You can see bands on CBC
 Bacterial infections cause ↑ neutrophils
 Parasitic and allergic responses cause ↑ eosinophils
 Viral infections usually ↓ neutrophils (can cause neutropenia)
o Typical with early COVID cases
 Severe infections can cause leukopenia
 Lymphadenopathy may occur
o Depending on site or initial inflammatory injury presence; lymph nodes below the site of injury are
enlarged
 Sepsis and septic shock (most severe)
 Elevated bands w/fever and abdominal pain  more acute; bandemia noted on CBC
 Nausea vomiting diarrhea, ↓neutrophils, ↑ lymphocytes  more viral
 ESR/CRP
o CBC inflammatory mediators

Tissue Repair and Wound Healing

 Response to tissue injury, attempt to maintain normal structure and function
 My involve regeneration and this is when cells are replaced by cells of the same type, typically
leaves no evidence of prior injury
 May involve replacement by connective tissue leaving a scar

Stages of Wound Healing

Healing via Primary/Secondary Intention

Primary healing (primary intention)  small, clean wound
 oEx. Sutured surgical incision.
Secondary healing (secondary intention)  larger loss of tissue, possibly contaminated.
o Slower than primary intention; wound edges are NOT brought together
o Results in the formation of larger amounts of scar tissue
 Ex. Diabetic foot wounds, pressure sores
 Bite wounds  jagged non clean wound on soft tissue surface
 Worry for infection; child bites are usually superficial, adult bites have
more serious injury
o Tx for bites: Irrigation, debridement of damaged tissue,
Augmentin
 Facial wounds are closed for cosmetic reasons; usually
they are allowed to heal by secondary intention

Causes of Impaired Wound Healing

 Malnutrition
 Impaired blood flow and oxygen delivery
 Impaired inflammatory and immune responses
 Infection
 Wound separation
 Foreign bodies
 Age

Terminology
 Host—any organism capable of supporting the nutritional and physical growth
requirements of another organism.
 Infectious disease—the disease state brought about by the interaction with another
organism.
o Influenza A causes development of influenza
 Colonization—the presence and multiplication of a living organism on or within the
host
 Microflora—bacteria inhabiting exposed surfaces of the body.
 Virulence—the disease-inducing potential or disease severity
 Pathogen—microorganisms capable of causing disease.
 Mutualism—an interaction in which the microorganisms and the host both derive
benefits from the relationship.
 Commensalism—an interaction in which colonizing bacteria acquire nutritional needs
and shelter, but the host body is not affected.
 Parasitic relationship—only the infecting organism benefits from the relationship.
The host does not benefit; even injured.
o When the host sustains injury from parasitic infection it is infectious disease

Microorganisms
 Eukaryotes  contain membrane bound nucleus
o Fungi, parasites, human cells
 Prokaryotes  do not have a defined nucleus
o Bacteria
  Both organisms can replicate and manufacture cellular metabolic energy.

Common Pathogens
 Prions
o Discovered in 1982
o Protein particles that transmit infection by self-replication
 Viruses
o Smallest pathogens
o Have no organized cellular structure
o Consist of a protein coat surrounding a nucleic acid core of DNA or RNA
o Incapable of replication
 Bacteria (Prokaryotes)
o Autonomous replication
o Smallest of all living cells
o Different morphologies include diplococci, staphylococci, streptococci, bacilli and
spirilla
 Rickettsiaceae/Chlamydiaceae
o Combine characteristics of viral and bacterial agents
 Fungi
o Free living eukaryotic
o Can be part of normal human microflora
o Usually causes disease of the skin and subcutaneous tissue
 Athletes foot, ring worm, tinea scalp
o Serious infections are rare  r/t puncture wounds or inhalation
o Can cause life threatening illness in immunosuppressed patients
 Ex. Pneumocystis pneumonia (PCP) and HIV patients
 Parasites
o Infect and cause disease in other animals including protozoa (malaria, dysentery)
o Helminths (worm like tapeworms)
 ingestion of eggs, walking with open wound and parasitic worm entering
o Arthropods (mites/scabies, lice and fleas)

Classification of Bacteria
According to microscopic
appearance of the cell with
staining
 Gram-positive
organisms: stained
purple by a primary basic
dye (crystal violet dye)
o Streptococcus –
causes scarlet
fever and
rheumatic fever
 Gram-negative
organisms: not stained
by the crystal violet but
are counterstained red by
a second dye (safranin
dye)
 o Legionella – causes Legionella pneumonia; gram negative rod

Common Pathogens 
Epidemiology (Terminology)
 Epidemiology – the study of factors, events and circumstances that influence the
transmission of infectious diseases among humans
 Incidence – the number of new cases of an infectious disease that occur within a defined
population
 Prevalence – the number of active cases at any given time

Incidence of Disease
Endemic disease: found in a particular geographic region
o The incidence and prevalence are relatively stable within that particular region
Epidemic: abrupt and unexpected increases in the incidence of disease over endemic
rates
o Same location but abrupt ↑
Pandemic: spread of disease beyond continental boundaries  COVID

Triad Infectious Disease Model

 Infectious disease result from the interaction of an
agent (pathogen), a susceptible hose and
environmental conditions that promote infection
o ***weakened immune system***
 Includes: type of pathogen, portal of entry and
competence of the hosts immune system

Mechanisms of Infection
 Portal of entry: how the pathogens enter the body
o Does not necessarily dictate the site of infection.
 Ex. Infected pathogens may penetrate GI mucosa and cause disease in the lung or
liver
 Direct transmission (STI’s) vs indirect transmission
 Modes of Transmission
o Penetration  disruption of the skin or mucous membrane
o Direct contact  direct from infected tissue, secretions
 Ex. Secretions from STI’s such as gonorrhea, chlamydia, syphilis
o Ingestion  entering through the oral cavity
 Hep A can be transmitted fecal oral route; mainly effects liver despite minor GI
manifestations.
 o Inhalation  infection through the respiratory tract
 Ex. Bacterial pneumonia, viral infections

Infectious Disease
 Location
o Nosocomial: develop in hospitalized patients
o Community acquired: acquired outside of health care facilities  pneumonia (antibiotic treatment is
tailored depending on location; inpatient care vs home when infection occurred)
 Broad spectrum to more tailored approach
 Source
o The location, host, object or substance from which the infection was acquired.
o May be endogenous  due to the persons own microflora (considered opportunistic infection)
o May be exogenous  pathogen enters the body from the environment.

Disease Course  Pathogen entered host

Incubation Period
o Pathogen begins replication without producing symptoms.
o Time from exposure to the onset of symptoms
 HIV incubates for months to years
 Influenza incubates in 1-4 days
 Salmonella incubates fast; symptoms within 6 hours and last 6 days
Prodromal Stage
o Initial appearance of symptoms in the host including fever, myalgia, headache and fatigue
 Patients are infectious!
o Infectious agent replicates and triggers the body’s immune response.
o Duration depends on infection
Acute Stage
o Host experience maximum impact of infectious process
o Maximum level of immune response from the host
 Immune system is most responsive
o Disease is most clinically evident
 Fever, fatigue, headache; symptoms vary based on underlying cause
o Timeframe depends on type of infection and number of infectious particles present
Convalescent Stage
o Containment and elimination of pathogen as well as repair
o Timeframe: pathogen dependent and host immune system response
 Can take days to months
 May be permanent damage
Resolution Stage
o Total elimination of the pathogen; no s/s of diseases
 This is when some disease states become chronic infectious disease states
 Because there is never full elimination of pathogen from the body

Disease Diagnosis
 Definitive diagnosis of an infectious disease requires recovery and identification of the infectious
organism by microscopic identification via culture, biopsy or presence of viral DNA/RNA (HIV, RSV,
HPV, COVID, etc)
 Treatment is based on source of infection and infectious microorganism
o May include antimicrobial agents, immunotherapy and surgical intervention
o Goal of treatment is elimination of source of infection and recovery
o Also may include supportive measures such as hydration, rest, nutrition
 Disease prevention is achieved via immunization
 Surgical intervention for severe disease  only intervention available before antibiotics
o Goal is to stop rapid disease spread; ex. Necrotizing fasciitis
 o Abscess  drainage of affected pocket; you give PO antibiotics for the secondary cellulitis
from primary abscess

Antibiotics
 Mechanism of action
o Interferes with a specific step in bacterial cell wall synthesis
o Inhibition of bacterial protein synthesis
o Interruption of bacterial nucleic acid synthesis
o Interference with normal bacterial metabolism
 Classification of action
o Bactericidal – causes irreversible and lethal damage to the bacterial pathogen
o Bacteriostatic – inhibitory effects on bacterial growth are reversed when the agent is
eliminated
 Classification and Target Sites
o Penicillin: cell wall
o Cephalosporins: cell wall
o Monobactams: cell wall
o Aminoglycosides: ribosomes
o Tetracyclines: ribosomes
o Macrolides: ribosomes
o Sulfonamides: folic acid synthesis
o Glycopeptides: ribosomes
o Quinolones: DNA synthesis
 Example: Cephalosporin taken for toothache, but penicillin is more appropriate for dental infection
and may not kill all bacteria there

Drug Resistance  broad spectrum antibiotics when not needed, invading organism has
developed resistance.

 Bacterial resistance mechanisms work by:

o Inactivating antibiotics
o Genetic mutations that alter the antibiotic binding sites
o Altering metabolic pathways bypassing antibiotic activity
o Changes in the bacterial cell wall that cause antibiotics to become ineffective.
 Broad spectrum need to be narrowed as fast as possible
 Antiviral resistance mechanisms work by:
o Mutation causes changes in the virus and the antiviral will not recognize the new virus.
o Need for combination therapy with multiple antiretroviral agents.
 AKA altering therapy such as HIV
 Difficult at first due to host toxicity  can damage host cells while stopping certain
replication.
 HIV  protease inhibitors
 Different changes to the virus; still antiretroviral will not work

Immunity
 The collective, coordinated response of the cells of the immune system
 Innate immunity (natural)
o The immunity that is in place before an encounter with an infectious agent
o Allows for a rapid response to the pathogen
 Adaptive immunity (secondary)
o Immunity that is acquired through previous exposure to infection.
o Can distinguish self from non-self and destroy specific pathogens
o Relies on previous exposure
o Two types of adaptive immunity include humoral and cell mediated immunity
 ***

Immunity Continued
 An intact innate (natural) immune response is essential to activate the adaptive (acquired)
immune response.
 Communication between the two systems occurs via Dendritic cells (DCs) which release
cytokines and chemokines.
 Cytokines and chemokines communicate information about the infecting microorganisms
to the B & T lymphocytes.
o Key part of adaptive immunity
o They activate additional lymphocytes/phagocytes to defend against infection

Immune Response
 Cytokines
o Essential for communication between cells
o Soluble proteins secreted by cells of both the innate and adaptive immunity
o Include interleukins (ILs), interferons (IFNs) and tumor necrosis factor alpha (TNF-a)
o They are self-limiting and synthesized when cells are activated
 o Pleiotropic: can act on different cell types
o Redundancy: different cytokines have similar effects and overlap
 Colony-stimulating factors
o Subset of cytokines that stimulate the growth and production of platelets, erythrocytes,
lymphocytes, neutrophils, monocytes, eosinophils, basophils and dendritic cells (DCs)
 Chemokines
o Responsible for directing the migration of leukocytes to their site of action
 Tell white blood cells where to go to fight the infection
o Chemokines are groups into four types (there are 48 distinct chemokine molocules)
 C, CC, CXC, CX3C
 CC chemokines attract monocytes, lymphocytes and eosinophils to sites of
chronic inflammation
 CXC attracts neutrophils to sites of acute inflammation
o Binding of a chemokine to a receptor can cause inhibition or activation of a cell
o Implicated in the development of acute and chronic disease
 Ex. Atherosclerosis, RA, UC, MS

Innate (Natural) Immunity

 The physical, chemical, cellular, and molecular immune system which produces a rapid
initial defense against infection.
 The innate immune system can distinguish between self and non-self but not able to
distinguish between different pathologic agents.
 Relies on the body’s ability to identify pathogen associated molecular patterns (PAMPs) present on the surface
of pathogens from normal human cells.
 Uses pattern recognition receptors (PRR) that recognize microbial structures (sugars, lipids, proteins) not
present in human cells.
o Once the PAMP are recognized the PRRs send intracellular messages to the host that cause
proinflammatory and antimicrobial responses which include the release of cytokines and chemokines
 Parts of innate/natural immunity
o Epithelial barrier
 The physical barrier that prevents the entry of organisms includes the skin,
cells that line the respiratory, GI and GU, mucous secreting goblet cells.
o Leukocytes
 Granulocytes  neutrophils, eosinophils and basophils
 Neutrophils are early responder cells; ↑ most seen with bacterial
infections.
 Basophils release histamines; more present in allergic type responses
 Eoosinophils recognize antigen antibody complexes and ↑ in viral
infections.
 Agranulocytes  monocytes and macrophages
 Neutrophils and macrophages are phagocytic meaning they engulf and digest
microbes.
o Dendritic Cells
 Specialized cells found in lymphoid tissue and function as a bridge between
innate and adaptive immune responses.
o Natural Killer (NK) Cells
 NK cells can spontaneously kill intracellular pathogens/microbes.
 First line of defense against viruses; can kill tumor cells and abnormal body
cells

Adaptive Immunity
 Immunity from previous exposure
 Able to recognize and react to different microbes and nonmicrobial substances.
 Ability to remember pathogens and produce a heightened immune response when there
are future exposures due to antigens.
o Substance or molecules that are foreign to the body causing an adaptive immune
response.
o When detected trigger the production of antibodies  takes about 14 days to
produce antibodies
o Recognized by receptors on the surface of B&T lymphocytes
o Antigens can include bacteria, fungi, viruses, protozoa, parasites, pollens, insect
venom and transplanted organs.
 Immunity can be developed through immunization/illness called active immunity.
 Immunity when the host receives antibodies or immune cells from another source is called
passive immunity.
o Breast feeding, IVIG, monoclonal antibodies
 T&B Lymphocytes are the main types of adaptive immune cells.
 Adaptive immune responses are humoral or cell mediated.
o Humoral immunity  B cells/extra-cellular microbes
 Mature B lymphocytes able to recognize antigens.
 B lymphocytes respond to extracellular microbes and their toxins
 The main defense against extracellular microbes and toxins
 Circulating antibodies interact with and destroy microbes.
o Cellular Immunity  T cells/intracellular microbes
 Cell mediated immunity.
 Mediated by cytotoxic T lymphocytes.
 Defends against intracellular microbes such as viruses.
 T cells recognize viruses based on infected cells surface peptides
 Controls the spread of intracellular viral replication.
o Both B and T cells develop memory for any subsequent exposures
 T Lymphocytes
 A part of cellular immunity
 The control of spread of intracellular viral replication
 Involved in the activation of autoimmune processes
 Involved in the rejection of foreign tissue grafts
 Delayed hypersensitivity reactions
 T cells are produced in bone marrow but mature in the thymus gland
 T cell include:
o Helper T cells (CD4 cells)
 Main cell activated in humoral cell mediated response
o Regulatory T cells 
 Limit inflammation & tissue damage
 Prevent excess immune activation
 Regulate number of cells that respond to an inflammatory
event
o Cytotoxic T cells (CD8 cells)
 Destroy any cells that threaten the integrity of the body.
 Monitor all cells in the body
o For cell mediated response you need all cell types working together

 Adaptive Immunity is either Active or Passive

 o Active Immunity
 Specific protection induced following exposure to an antigen through disease
or immunization
 B lymphocytes develop antibodies to the exposure
o Passive Immunity
 When a person is given antibodies to a disease rather than producing them
through his or her own immune system  transferred to host such as mother
to fetus
 Transfer of protective antibodies against an antigen
 Maternal IgG (IgG = monoclonal antibodies) crosses the placenta and
protects the newborn during the first few months of life
 IgA in the colostrum during breast feeding
 Additional examples include IVIG or monoclonal antibodies

The Complement System

 Works with both the innate and adaptive immune system
 Helps the body contain infection and destroy the microorganism
 Made up of proteins found in the blood and extracellular fluids which are normally
circulating in their inactive form
o When activated leukocytes migrate to the infection, a localized inflammatory
reaction occurs and the pathogen is destroyed
 Primary function of the complement system is the promotion of inflammation and the
destruction of microbes

Function of Lymphoid Organs

Central: bone marrow and thymus
o Environment for immune cell production and maturation
o Thymus: aids in T lymphocyte maturation
 Fully developed at birth, most active neonatal and adolescence
 Begins to atrophy at puberty.
 Residual T cell production continues throughout adult life but is less
significant.
Peripheral: trap and process antigens
o Interact with other immune cells for recognition.
o Lymph nodes
 Cellulitis in the arm could have swollen or sore axillary nodes

Immune System Development

 Begins early in fetal development at 5 to 6 weeks
 Secondary lymphoid organs (spleen, lymph nodes, lymph tissue) are well developed at
birth but small
 Develop rapidly during the postnatal period when exposed to microbes
 Neonatal immune response is through the transfer of maternal IgA and IgM antibodies
shortly after birth
o Maternal IgA antibodies continue to be transferred via colostrum and breast milk
o Maternal vaccinations offer passive immunity against infections like influenza
 Elderly Immune System
o Cannot rule out fever in older adults due to ↓immune response
 Can have infection and no presence of fever
o Immune function declines
 o Altered response to antigen stimulation
o Less likely to develop strong immune response to vaccinations

Immunodeficiency States
 Abnormality in the immune system that results in an ↑susceptibility to disease
 Adaptive immune system relies on humoral B cell-mediated immune as well as cell-
mediated T cell responsiveness
o Primary (congenital or inherited)
 Termed primary immunodeficiency diseases (PIDDs)
 Sex-linked, autosomal dominant, or autosomal recessive traits
o Secondary (acquired due to pathologic conditions)
 Malnutrition
 Infection (ex. AIDS)
 Neoplastic disease (ex. Lymphoma)
 Immunosuppressive therapy (ex. Corticosteroids or transplant rejection
medications)

Humoral (B-cell) Immunodeficiencies

 Associated with B cell dysfunction and ↓IgG production
 Extracellular immunity
 B lymphocytes are essential for defense against bacteria
o People with humoral deficiencies are at risk for recurrent bacterial infections
 Ex. S pneumoniae, H influenza
 Humoral immunity is not as important in defending against intracellular bacteria
(mycobacteria), fungi, and protozoa
o Recurrent infections with these organisms is less likely
 T cell function is normal (cellular immunity) response to most viruses are normal
 Primary Humoral Immunodeficiency Disorders
o Genetic disorders of the B lymphocytes
o 70% of primary immunodeficiencies
o Immunoglobulin production depends on:
 The differentiation of immature stem cells with the IgM surface to mature B
lymphocytes with IgG, IgA, or an IgE surface
 Generation of immunoglobulin-producing plasma cells
 Immunodeficiency disorders can interrupt the production of B lymphocytes
one or all the steps in immunoglobulin production.
 Prevent immature B cell from turning into mature IgA, IgG or IgE
o Transient Hypogammaglobulinemia of Infancy (THI)
 There is a reduction in one or more serum Ig levels resulting in recurrent
infections
 Symptoms manifest as maternal IgG antibody levels decline during the first 6
months of life
 Clinical manifestations
 Lower respiratory tract infection such as pna, allergies and allergic
asthma
 Tx with prophylactic antibiotics  new evidence supports IVIG (passive
immunity)
  Most cases of THI resolve spontaneously by 3 years of age

 Common Variable Immunodeficiency

o Primary immunodeficiency associated with impaired B-cell differentiation and
antibody production
o Heterogeneous disorder affecting men & women equally
 No one specific gene mutation has been identified
o Impaired antibody response to infections and vaccine challenge  no memory
development from exposure
o Clinical manifestations of CVID can occur at any stage of life
o Persons commonly experience recurrent bacterial and viral infections from the
respiratory tract
o Additional disease process associated with CVID include autoimmune diseases
(27%)
 Most commonly autoimmune hemolytic anemia (AIHA) and autoimmune
thrombocytopenic purpura
 Also inflammatory arthritis, inflammatory bowel disease or vasculitis.
o Treatment for CVID is like treatment for other primary humoral immunodeficiencies.
 IVIG is the mainstay of therapy.
 Infusion of passive immunity

 Secondary Humoral Immunodeficiency Disorders (acquired)

o Multiple causes  malnutrition, burns, GI loss, nephrotic syndrome, malignancy,
medication side effects
 Prolonged steroids, antiepileptics, antihypertensives, chemotherapy,
immunotherapy
o Nephrotic syndrome
 Kidneys cannot filter the IgG back into the bloodstream d/t abnormal
glomerular filtration
 Lost in urine
 Serum IgM and IgA are normal or elevated to compensate; not lost because
they do not pass through kidney filtration process

Cell Mediated (T cell)

Immunodeficiencies 

 Primary cell mediated Immunodeficiency Disorders

o T cell disorders are often the most severe
 o Patients often die from serious viral, fungal, and opportunistic infections within the
first few months of life
o Maternal antibodies offer no protection against the cell mediated disorders
o One example:
 Severe combined immunodeficiency disorder  rarely survive beyond infancy
or childhood 2/2 infection
o Bone marrow transplant is the treatment of choice in children with severe forms of
T-cell immunodeficiency
 More recently, stem cell transplant and gene therapy is used

 Secondary cell-mediated immunodeficiency disorders

 Regardless of the cause people with secondary cell mediated

immunodeficiency disorders have an increased susceptibility to
opportunistic infections (pathogens that do not normally cause
infection in humans)

 Combined T-Cell & B-Cell immunodeficiencies  defect in

humoral and cell mediated response

Defect in both B cell and T cell functioning

Disorders of the Complement System  allows body to localize and destroy invading organism
• Primary
 • Inherited autosomal dominant trait
• Hereditary angioneurotic edema (HAE) a rare life-threatening condition that results in
spontaneous swelling in subcutaneous tissues.
• Ex: laryngeal edema which can be life threatening.
• Secondary
• Can occur in persons with functionally normal complement systems because of rapid
activation and turnover or reduced synthesis of complement components.
• Can be seen in chronic liver disease or severe malnutrition.

Hypersensitivity Disorders
Excessive or inappropriate activation of the immune system causing damage to
the host.
Types
o Type I, IgE-mediated disorders
o Type II, antibody-mediated disorders
o Type III, complement-mediated immune disorders
o Type IV, T-cell–mediated disorders
Type 1 Hypersensitivity Disorders
o Classic allergic response  abnormal exaggerated response
 Caused by IgE mediated activation of mast cells and basophils with the
release of chemical mediators causing an inflammatory response.
o Atopic Disorders
 Heredity predisposition.
 Localized reaction to IgE antibodies produced in response to
common environmental agents
 Urticaria (hives), allergic rhinitis (hay fever), atopic dermatitis,
food allergies, some forms of asthma
o Allergic Rhinitis:
 Common hypersensitivity disorder of upper respiratory tract
 Allergic response starts in the nasal mucosa when aeroallergens are
inhaled causing ↑ IgE production.
o Nonatopic Disorders
 Lack the genetic component and organ specificity of the atopic
disorders
o Types of type 1 responses
Food Allergies

***ANY food can cause

reaction: most
common is peanut,
tree nut or shellfish

Type II Hypersensitivity Reactions

o Action
 Mediated by IgG or IgM antibodies directed against target antigens on the
surface of cells or tissues
 Endogenous antigens: present on the membranes of body cells
 Exogenous antigens: absorbed on the membrane surface
o Examples
 Mismatched blood transfusion reactions
 Hemolytic disease of the newborn
 Certain drug reactions, Hashimoto’s disease, Good pastures syndrome

Type III Hypersensitivity Reactions

o Mediated by the formation of antigen–antibody complexes which are deposited in
tissues & then activate the complement pathway
 Immune complexes formed in the circulation produce damage when in they
meet the vessel lining or are deposited in tissues since they
o They elicit an inflammatory response by activating the complement pathway.
o Leading to the recruitment of neutrophils and other inflammatory cells.
o Cause alterations in blood flow
o Cause ↑ vascular permeability
o Destructive nature of inflammatory cells
o Responsible for the vasculitis seen in certain autoimmune diseases

Type IV Hypersensitivity Reactions

o Cell-Mediated Immune response that is delayed
  Different from type I & II reactions that are antibody-mediated and
immediate immune responses
o The primary immune response to a variety of microorganisms
 Intracellular pathogens (M. Tuberculosis/viruses)
 Extracellular microorganisms (fungi, protozoa)
o Can lead to cell death and tissue injury in response to antigens
o Cell mediated immune responses with T lymphocytes cause cell and tissue
injury
 Intracellular reactions
o Examples:
 Allergic contact dermatitis
 Hypersensitivity pneumonitis
 Stevens Johnson Syndrome

Transplanted Tissue
Transplantation can be defined as the process of taking cells, tissues or organs
known as a graft from one person and placing them into another person to restore
body function
o Allogeneic
 The donor and recipient are related or unrelated but share similar HLA
types.
o Syngeneic
 The donor and recipient are identical twins.
o Autologous
 The donor and recipient are the same person.

Patterns of Transplant Rejection

o Hyperacute Reaction
 Occurs almost immediately after transplantation.
 Produced by existing recipient antibodies to graft antigens initiating a
type III hypersensitivity reaction (antigen-antibody reaction)
o Person who receives the tissue has antibodies to the antigens
present in the transplanted tissue
o Acute Antibody-Mediated Rejection
 Occurs days to weeks after transplant, dependent upon whether the recipient
received immunosuppressive therapy before the transplant.
o Chronic Rejection
 Immune mediated inflammatory injury to a graft occurring over a long period
of time.
 Occurs because there is not adequate immunosuppression to control antigraft
T cells or antibodies.
 Progressive decline in tissue function due to vascular injury and impaired
blood supply.

Graft vs Host Disease

o GVHD is a major complication.
  Often occurs after allogeneic stem cell transplant. Can also occur in
solid organ transplants such as liver
o Three basic requirements for the development of GVHD
 Doner cells must be immunologically competent
 Recipient cells must have antigens to the foreign donor cells/tissue
 The recipient must be immunologically compromised & not able to
mount an effective immune response
o Occurs over a prolonged period.
o Manifests with dense intimal fibrosis of blood vessels of the transplanted
organ.
o Can be acute (within the first 100 days) or chronic (after the first 100 days)
o Clinical Manifestation
 Patient may present with pruritic rash starting on the hands/feet. GI
symptoms may include nausea, anorexia, diarrhea and abd pain. Can
progress to the development of veno-occlusive disease, sepsis or
coma.
o Severe GVHD is associated with a poor prognosis and long-term survival rate
of 5%.

Autoimmune Diseases

A group of disorders that occur when the body’s immune system fails to differentiate
self from non-self, mounting an immune response against host tissues.

Autoimmune diseases can be caused by:

Heredity
Gender (women)
Failure of immune self-tolerance causing damage to body tissues
Environmental factors (viral infection, lack of maternal antibodies from breast-feeding, smoking and exposure to
chemicals)

Examples include:
Systemic lupus erythematosus (SLE)
Autoimmune hemolytic anemia (AIHA)
Hashimoto thyroiditis

Criteria for Evidence of an autoimmune reaction

Diagnosis
Determination that the immunologic findings
are not secondary to another condition

The lack of other identified causes for the

disorder

Symptoms are non-specific and often overlap other conditions

 Corticosteroids often used for treatment

The AIDS Epidemic and Transmission of HIV Infection

Pathophysiology and Clinical Course

o Molecular and Biologic Features of HIV

 HIV is an retrovirus that replicates by integrating its self into the host.
 CD4 & helper T cells are affected
 CD4 cells are necessary for normal immune function.
 CD4 count and viral load is how we measure the HIV progression
 Maternal ART can reduce transmission from 25% to 1%

o Two types of HIV include HIV-1 and HIV-2

 HIV 1 responsible for the most HIV infections worldwide. Most often associated with
AIDS in the US, Europe & Central Africa
 HIV 2 is most common in West Africa. Patients less likely to develop AIDS
 In some areas of West Africa both types are present
 Type 2 is less virulent

o Phases of HIV Infection (occurring over 8-12 years)

1. Primary infection phase- pt. may have a flu like illness that resolves
o May not seek treatment or be misdiagnosed as viral syndrome

2. Chronic asymptomatic or latency phase-can last for many years.

o The end of the latent period is marked by onset of opportunistic
infections or cancers.

3. Overt AIDS phase is the presence of opportunistic infections

o P.carinii pneumonia, cryptococcal meningitis, Kaposi sarcoma, or
others.

Prevention, Diagnosis and Treatment

 Prevention is important since there is no cure
 PREP: people who are not infected but at high risk of infection
 o Partner with HIV, multiple partners
 Diagnostic Methods
 Enzyme immunoassay (enzyme-linked immunosorbent assay)
 Western blot antibody detection tests for HIV infection
 Treatment  goal: extend latent period, preserve immune function, prevent
opportunistic infections
 Reverse transcriptase inhibitors
 Protease inhibitors
 Fusion inhibitors