Week 2
Immunity
Innate Immunity
• Simplistic, nonspecific immunity present at the
time of birth
– Natural killers cells
– Various mechanical barriers
– Phagocytic cells (neutrophils and phagocytes)
– Protective proteins
Acquired Immunity
• based on specific responses elicited by
antigens
• Antigen: any chemical substance that can
produce a specific immune response
• Based on body’s ability to distinguish between
self and non-self
Immune Response
• Natural immunity
– Defense mechanism
– Properdin
– Lysozyme
• Acquired immunity
– Self versus non-self
Cells of the Immune System
• Bone marrow stem cells develop into
lymphoid cells and other hematopoietic cells
• lymphoid cells are the primary cells of
immunity
• Lymphocytes: derived from bone marrow
Cells of the Immune System
• Lymphocytes
– T lymphocytes
• T helper cells (CD4)
• T suppressor/cytotoxic cells (CD8)
• Natural killer (NK) cells
• B lymphocytes
• Plasma cells
• Macrophages
Immune System
Maturation of T & B
Lymphocytes
Antibodies
• Five classes of immunoglobulins:
1.IgG
2.IgM
3.IgA
4.IgE
5.IgD
Antibodies (Cont’d)
• All composed of light & heavy chains
– Light chains: same
– Heavy chains: specific for each Ig
• Each chain has constant (Fc) & variable region
(Fab)
T Cell Lymphocytes
• Matured in the thymus
• Several different types
• 2/3 of all lymphocytes in blood
• Located in blood, lymph nodes, and
spleen
• T-cell receptor on cell surface used for
recognition of antigens
B Cell Lymphocytes
• Differentiate into immunoglobulin
producing plasma cells
Plasma Cells: Antibodies
• Proteins secreted by plasma cells
• Any substance seen as foreign may
serve as an antigen and create an
immune response
• The antigen will bind to b- lymphocyte
antigen receptor
• This signals the production of the
antibody
Diagram of Immunoglobulin
Major Histocompatibility
Complex (MHC)
• Essential for presentation of antigens to T cells
• Also known as human leukocyte antigen
(HLA)
• Two groups of MHCs:
1.Type I: receptors for CD8
2.Type II: react with CD4
Antigen-Antibody Response
• Antigens and antibodies are bound together
both physical and chemically
• Complexes usually enlarge in serum until
they are taken up and phagocytized by the
spleen and liver
Antigen–Antibody Reaction
• Antibodies to soluble antigens complexes; may
be found in circulation
• Antibodies bound to fixed antigens on cells
coat cell surface
• Antigen–antibody complexes bind & activate
complement, which is effector system: lysis of
cells, agglutination or recruitment of
inflammatory cells
Immune Hemolysis
Stress
• Universal experience
• Result of both positive and negative
experiences
• Important to understand
• Response to change
Stress Adaptation
• Hans Seyle
– Observed bodily changes produced by stress
• General adaptation syndrome
• Local adaptation syndrome
• Influenced by several factors
– Natural reserve, time, genetics, age, gender, health
status, nutrition, sleep–wake cycles, hardiness, and
psychosocial factors
Physiological Response
to Stress
• Fight-or-flight response
• Results from activation of the sympathetic and
endocrine systems
• Includes increased heart rate, increased
respirations, diaphoresis, increased blood flow
to muscles, increased muscle strength,
increased mental alertness, increased fat and
protein mobilization, increased glucose
availability, and decreased inflammation
Stages of General
Adaptation Syndrome
1. Alarm
– Initial reaction
– Sympathetic nervous system
2. Resistance
– Adaptation
– Limit stressor
3. Exhaustion
– Adaptation failing
– Disease develops
Local Adaptation Syndrome
• Local version of the general adaptation
syndrome
• Body’s attempt to minimize the damage of the
stress to a small location
Coping
• Ability to deal with the stressor
• Influenced by
– Genetics, age, gender, life experiences, dietary
status, and social support
• Adaptive coping strategies include
– Physical activity, adequate sleep, optimal dietary
status, relaxation, distraction, and biofeedback
• Maladaptive coping strategies include
– Smoking, substance abuse, and overeating
Immune System
• Self-regulated
• Self-limiting
• Must be able to distinguish self from nonself
• Antigens
• Two major actions: defending and attacking
Innate Defense Barriers
(1 of 2)
• Nonspecific
• Immediate response
• Distinguish self from nonself
• Do not distinguish between pathogens
• Include
– Skin and mucous membranes
– Chemicals
Innate Defense Barriers
(2 of 2)
• Physical and chemical barriers not completely
impenetrable
• Additional bloodborne innate defenses include
– Inflammatory response
– Pyrogens
– Interferons
– Complement proteins
Inflammatory Response
• Vascular reaction.
• Triggered by mast cells.
• Manifestations include erythema, edema,
warmth, heat, and pain.
Pyrogens
• Fever-producing molecules
• Produced by macrophages
• Create an unpleasant environment for bacterial
growth
• Severe fever—life-threatening
Interferons
• Proteins released from virus-infected cells.
• Bind to nearby uninfected cells.
• The uninfected cells release an enzyme that
prevents viral replication.
• When the virus infects these cells, they are
unable to replicate.
Complement Proteins
• Plasma proteins that enhance antibodies
• Activated by antigens
• Play a role in the immune and inflammatory
response
Adaptive Defenses
• Specific
• Develop over time
• Use memory system
• Distinguish self from nonself and between
pathogens
• Include
– T cells: cell-mediated immunity
– B cells: humoral immunity
Cellular Immunity
• Mediated by T cells on recognition of antigen.
• T cells are produced in bone marrow and mature in
the thymus.
• Two types
– Regulator: T helper, T suppressor
– Effector/killer
• T cells protect against viruses and cancer.
• T cells are responsible for hypersensitivity reactions
and transplant rejections.
Humoral Immunity
• Mediated by B cells on encountering antigen.
• B cells mature in bone marrow.
• B cells differentiate into two types
– Memory cells
– Immunoglobulin-secreting cells
• Antibodies are produced 72 hours after initial
antigen exposure.
• Subsequent exposure to same antigen leads to
quicker response (memory cells).
Acquired Immunity
• Active immunity
– Acquired by having the disease (i.e., prior antigen
exposure) and by vaccinations
– Long lasting but takes a few days to become effective
• Passive immunity
– Receiving antibodies from external sources: maternal–fetal
transfer of immunoglobumins and breastfeeding
– Short lasting
Alterations in Immunity
• Hypersensitivity
– Exaggerated immune response to a foreign
substance
• Autoimmune
– Mistakes self as nonself
• Immunodeficiency
– Inadequate immune reaction
Hypersensitivity
• Inflated response to antigen
• Leads to inflammation, which destroys healthy tissue
• Can be immediate or delayed
• Four types:
– Type I: IgE mediated
– Type II: cytotoxic hypersensitivity reaction
– Type III: immune complex–mediated
– Type IV: delayed hypersensitivity reaction
Types of Hypersensitivity
(1 of 6)
• Type I, IgE mediated
– Produces an immediate response.
– Local or systemic.
– Allergen activates T-helper cells that stimulate B cells to
produce IgE.
– IgE coats mast cells and basophils, sensitizing them to the
allergen.
– At next exposure, the antigen binds with the surface IgE,
releasing mediators and triggering the complement system.
Types of Hypersensitivity
(2 of 6)
• Type I, IgE mediated
– Repeated exposure to large doses of allergen is
necessary to cause this response.
– Examples:
• Hay fever, food allergies, and anaphylaxis
– Treatment includes epinephrine, antihistamines,
corticosteroids, and desensitizing injections.
Type I Hypersensitivity
Diseases Caused by Type I Hypersensitivity
Reactions
• Hay fever
• Asthma
• Atopic dermatitis
• Anaphylactic shock
Atopic Reactions
Types of Hypersensitivity
(3 of 6)
• Type II, cytotoxic hypersensitivity reaction
– IgG or IgM type antibodies bind to antigen on
individual’s own cells.
• Antigen may be intrinsic or extrinsic.
– Recognition of these cells by macrophages triggers
antibody production.
– Lysis of cells occurs because of the activation of
the complement and by phagocytosis.
– Usually immediate responses.
Types of Hypersensitivity
(4 of 6)
• Type II, cytotoxic hypersensitivity reaction
– Examples:
• Blood transfusion reaction and erythroblastosis fetalis
– Treatment includes ensuring blood compatibility
(transfusion) and administering medication to
prevent maternal antibody development (Rho[D]).
Type II Hypersensitivity
Diseases Caused by Type II Hypersensitivity
Reactions
• Hemolytic anemia
• Goodpasture’s syndrome
• Graves’ disease
• Myasthenia gravis
Goodpasture’s Syndrome
• Autoimmune
• antibodies attack the
basement membrane
in lungs and kidneys
• leads to bleeding
from the lungs and
kidney failure.
Types of Hypersensitivity
(5 of 6)
• Type III, immune complex–mediated
hypersensitivity reaction
– Circulating antigen–antibody complexes
accumulate and are deposited in the tissue.
– Triggers the complement system, causing
inflammation.
– Example:
• Autoimmune conditions (e.g., systemic lupus
erythematosus)
– Treatment is disease specific.
Type III Hypersensitivity
• Accumulation of
antigen-antibody
complexes that
have not been
cleared by immune
cells
• Leads to
inflammatory
response and
attracts leukocytes
Diseases Caused by Type III Hypersensitivity
Reactions
• Systemic lupus erythematosus
• Post streptococcal glomerulonephritis
• Polyarteritis nodosa (vasculitis following
hepatitis B)
Types of Hypersensitivity
(6 of 6)
• Type IV, delayed hypersensitivity reaction
– Cell-mediated rather than antibody-mediated
involving the T cells.
– Antigen presentation results in cytokine release,
leading to inflammation.
• Causes severe tissue injury and fibrosis
– Examples:
• Tuberculin skin testing, transplant reactions, and contact
dermatitis
– Treatment is disease specific.
Type IV Hypersensitivity
• Delayed response (2-3
days)
• Cell Mediated Response
Clinical Examples:
•
Poison Ivy
• Autoimmune
Myocarditis
• Hashimoto’s Disease
• Inflammatory Bowel
Disease
Caseating Granuloma
• Collection of
histiocytes,
macrophages
• Immune cells surround
and encapsulate antigen
• Caseating= cheese-like
appearance
– Signifies necrosis within
the granuloma
– Signifies infectious
disease
Diseases Caused by Type IV Hypersensitivity
Reactions
• Infections with Mycobacterium tuberculosis,
Mycobacterium leprae, fungi (Histoplasma
capsulatum)
• Reaction to tumors
• Sarcoidosis
• Contact dermatitis
Acute Contact Dermatitis
Transplants
• Making the best match of tissue antigens is key for
success.
• Donor sources may be living or a cadaver.
• Four categories
– Allogenic: donor and recipient are related or unrelated, but
share similar tissue types
– Syngenic: donor and recipient are identical twins
– Autologous: donor and recipient are the same person; most
successful
– Xenogenic: use of tissue from another species
Transplantation
• Autograft
• Isograft
• Homograft (allograft)
• Xenograft
____________________________________
Note: Before allografting, test for
histocompatibility using HLA
antigenal
Patterns of
Transplant Reactions
(1 of 2)
• Hyperacute tissue rejection
– Immediate or three days after transplant
– Due to the complement system
– Tissue becomes permanently necrotic
• Acute tissue rejection
– Most common
– Treatable
– Occurs between four days and three months after transplant
– Manifestations: fever, erythema, edema, site tenderness,
and impaired function of transplanted organ
Patterns of
Transplant Reactions
(2 of 2)
• Chronic tissue rejection
– Occurs four months to years after transplant.
– Likely antibody-mediated response.
– Antibodies and complements deposit in vessel
walls of transplanted tissue, resulting in ischemia.
Transplant Reaction
Classifications
(1 of 2)
• Host vs. graft disease
– Host fights the graft.
– The recipient’s immune system attempts to
eliminate the donor cells.
Transplant Reaction
Classifications
(2 of 2)
• Graft vs. host disease
– Graft fights the host.
– Frequent and potentially fatal complication of bone marrow
transplants.
– Occurs when immunocompetent fatal cells recognize host
tissue as foreign and mount a cell-mediated immune
response.
– The host is usually immunocompromised and unable to
fight graft cells; the host’s cells are destroyed
• Treatment: Immunosuppressive therapy
Transplant Rejection
• Hyperacute reaction
• Acute reaction
• Chronic transplant rejection
Rejection of Transplanted
Kidney
• antigens responsible are
histocompatibility antigens
• both cellular (lymphocyte
mediated) and humoral
(antibody mediated)
mechanisms.
• Primarily T cells
• Inflammatory response is
initiated
• Apoptosis initiated
Clinical Use of Transplantation
• Kidney
• Skin
• Liver
• Heart
• Lung
• Pancreas
• Bone marrow
Graft-versus-Host Reaction
• Mediated by transplanted T lymphocytes
• Most often complication of bone marrow
transplantation
• Organs most often affected:
– Skin: exfoliative dermatitis
– Intestine: malabsorption, diarrhea
– Liver: jaundice
Blood Transfusion
• Major blood group antigens of type ABO have
natural antibodies against them preventing
transfusion between groups
• Minor blood group antigens
• Rh group has antibodies forming sensitization
• Crossmatching is important before transfusion
Major Blood Groups Determine
Outcome of Transfusion
Autoimmune Disorders
(1 of 2)
• Immune system loses the ability to recognize
self.
• Defenses are directed against host.
• Can affect any tissue.
• The mechanism that triggers this response is
not clear.
Autoimmune Disorders
(2 of 2)
• Known characteristics
– Genetics plays a role.
– More prevalent in females.
– Onset is frequently associated with an abnormal
stressor, physical or psychological.
– Are frequently progressive relapsing-remitting
disorders characterized by periods of exacerbation
and remission.
Autoimmune Diseases
Systemic Disease
- Systemic Lupus
- Rheumatic Fever
- Systemic Sclerosis
Organ Specific
- Brain: Multiple Sclerosis
- Thyroid: Hashimoto’s Thyroiditis
- Blood: autoimmune hemolytic anemia
- Kidney: glomerulonephritis
- Liver: primary biliary cirrhosis
- Muscles: myasthenia gravis
Autoimmune Diseases
• Abnormal response to self-antigens
• To make diagnosis, look for:
– Autoantibodies: may be present in blood
– Immune mechanisms (hypersensitivity): may play
important pathogenetic role
– Indirect evidence that disease has immune nature
(e.g., steroids help)
Incidence of Autoimmune
Diseases
• Familial: genetic predisposition
• Certain HLA: haplotypes more often linked to
autoimmune diseases; genetic aspects are
important
• Sex differences: more common in women than
men; shows nongenetic factors are obviously
also important
Autoimmune Diseases
• Systemic (multiorgan): SLE, rheumatic fever,
rheumatoid arthritis, systemic sclerosis,
• Limited to single organ:
– Multiple sclerosis: CNS
– Hashimoto’s thyroiditis, Graves’ disease: Thyroid
– Autoimmune hemolytic anemia: blood
– Pemphigus vulgaris: skin
– Myasthenia gravis: muscle
Systemic Lupus Erythematosus
(1 of 4)
•
•
•
•
•
•
Chronic inflammatory autoimmune condition.
May affect connective tissue of any body organ.
Remission and exacerbations—stressors tend to trigger.
Disease progression varies from mild to severe.
More common in women, Asians, and African Americans.
Cause is unclear, but it’s thought that B cells are activated to
produce autoantibodies and autoantigens that combine to form
immune complexes, which attack the body’s own tissues.
Systemic Lupus Erythematosus
(2 of 4)
• Diagnostic criteria (four
or more of the following)
– Serositis
– Oral ulcers
– Arthritis
– Photosensitivity
– Blood disorders
(decreased count)
– Renal involvement
– Immunological
phenomena
– Antinuclear antibody
– Neurological disorders
(seizures/psychosis)
– Malar rash (butterfly rash
over cheeks)
– Discoid rash (patchy
redness that can cause
scarring)
Systemic Lupus Erythematosus
(3 of 4)
• Diagnosis
– 11 criteria, X-rays, elevated sedimentation rate,
C-reactive protein, urinalysis, echocardiogram, and
blood test for complications
Systemic Lupus Erythematosus
(4 of 4)
• Treatment
– No cure—only symptom management
– Stress management and health promotion
behaviors
– Pharmacological
• NSAIDs, antimalarials, corticosteroids,
immunosuppressants, and DMARDs
– Plasmapheresis
• Prognosis improves with early diagnosis and
treatment.
Systemic Lupus
Erythematosus
Sjogren’s Syndrome
• Secondary autoimmune disease
– SLE, Scleroderma, Sarcoidosis, rheumatoid
arthritis
• Mostly effect post menopausal women
• Marked by excessive dryness and lack of
secretions from mucus membranes
• ANA’s “attack” tissue of mucus secreting
membranes
• Treated with corticosteroids and drugs to
increase secretions
Amyloid
• Inert extracellular material defined by
physical rather than biochemical
properties:
– Fibers 7.5 mm thick; seen by electron
microscope
– Stains with Congo red; appears apple
green under polarized light
– Beta-pleated sheet by radiographic
crystallography
– Biochemically can be AA amyloid, AL
amyloid, and many other forms of amyloid
Clinical Presentation of Amyloid
Deposition
• AL Amyloid: from immunoglobulins, seen in malignant
lymphoma
• AA Amyloid: from serum amyloid A proteins, produced
by the liver
• Deposits of amyloid change function of organs and
tissues
• Systemic amyloidosis: usually caused by deposition of
AA or AL amyloid in various organs (e.g., liver,
kidneys, adrenals, spleen, heart)
– Ischemia, atrophy, loss of function
– Weakened myocardium
– Hepatic and adrenal insufficiency
– proteinuria
• Localized organ: specific amyloid deposits (e.g.,
Alzheimer’s disease)
Amyloidosis
• Primary Amyloidosis: AL amyloid of multiple myeloma
– Deposited in kidneys, and in blood vessels of many organs
• Secondary Amyloidosis: AA amyloid deposits
– abnormal response to chronic infection
– Chronic tuberculosis, chronic osteomyelitis
– Kidneys, liver, adrenals, spleen, and blood vessels in many organs and
tissues
•
•
•
•
Symptoms depend on organ involved
Diagnosis is only by biopsy, difficult to biopsy
Amyloid imaging
Amyloidosis cannot be treated effectively.
Immunodeficiency
• Diminished or absent immune response
• Renders the person susceptible to disease
normally prevented
– Opportunistic infections
• May be acute or chronic
• Classifications
– Primary
– Secondary
Immunodeficiency Diseases
• Primary immunodeficiency diseases
(congenital)
• Secondary immunodeficiency diseases
(acquired)
– Result of infections, metabolic diseases, cancer
– AIDS is most common
• Lymphopenia: decreased lymphocytes in blood
– defective or inadequate T-cells, B-cell deficiencies
Primary Immunodeficiency
Diseases
• Severe combined immunodeficiency: defect of
lymphoid stem cells (pre-B, pre-T cells)
• Isolated deficiency of IgA: most common;
1:700; often asymptomatic
• DiGeorge’s syndrome: T-cell deficiency
related to aplasia of thymus, associated with
aplasia of parathyroid glands
AIDS
• HIV
– Parasitic retrovirus that infects CD4 and macrophages upon
entry
• Two primary types
– Type 1 is the most common strain.
– Type 2 is more common in West Africa; progresses to
disease more slowly.
• In the US, rates rising among women and African
Americans
• Transmission
– Blood and bodily fluids
Clinical Presentation of HIV & AIDS
• Acute illness
• Asymptomatic infection
• Persistent generalized lymphadenopathy
• AIDS: terminal phase with superimposed
infections
AIDS Progression
(1 of 2)
• Asymptomatic phase.
– Virus is reproducing, usually for several years.
• Infections begin as the viral number rises,
destroying the CD4.
• Progression takes three forms.
– Immunodeficiency
– Autoimmunity
– Neurological dysfunction
AIDS Progression
(2 of 2)
• Diagnostic test (used for diagnosis and for
determining progression)
– HIV antibody
• Rapid test
• Home test
• Polymerase chain reaction
– Measures amount of HIV DNA or viral load
– Good for infants and infected mothers
Course of HIV
HIV and AIDS: progression of
HIV
• Sharp decrease in CD4 T-helper cells in blood
• Prolonged period of clinical latency while Tcells continue to decrease until reaches a
critical level
• Helper T lymphocytes, macrophages,
monocytes fixed phagocytic cells all house
virus
• At critical level, immunosuppression leads to
opportunistic infections
4 phases of HIV
1. Acute Illness: 3-6 weeks post exposure
 Flu-like symptoms: night sweats, skin rash, nausea, myalgia, headache,
fever, sore throat, minor lymph-node involvement, some develop HIV
antibodies
 May have all or only one symptom
 Symptoms spontaneously subside in 2-3 weeks,
2. Asymptomatic Infection: lasts a few months to a few years,
3. Generalized Lymphadenopathy: may develop early and may
last for years,
 patients may be otherwise asymptomatic
4. AIDS: superimposed infections and complications
 Infections, GI disorders, CNS involvement, neoplasia
AIDS Classification System
• Two systems, one based
on lab findings and the
other based on clinical
manifestations
• Laboratory findings—
CD4 cell count
– Category 1: > 500
cells/μL
– Category 2: 200–499
– Category 3: < 200
• Clinical presentation
– Category A:
asymptomatic
– Category B: some less
serious manifestations of
immune deficiency
– Category C: AIDSdefining illnesses present
HIV and the brain
•
•
Brain shows specific changes to HIV
HIV evokes a response of microphages in the brain
– Formation of microglial nodules and multinucleated cells in gray matter and subcortical gray
matter of the cerebellum.
– Lesions caused by opportunistic infections lead to meningitis and encephalitis
– Viruses invade affect the brain: herpesvirus, cytomegalovirus, fungi, protozoa
• Attack the brain or occlude blood vessels leading to ischemic infarct
HIV and AIDS
• Respiratory Tract
– Early stages” rhinitis and pharyngitis
– Late states: pneumonia and tuberculosis
• Gastrointestinal Tract
– Diarrhea, malabsorption syndromes, protozoa and
worms
• Skin Lesions
– Vary from itchy skin rashes to persistent
infections
– Herpesvirus, fungi, streptococcal folliculitis
Pathologic
Findings
in AIDS
Tumors That Develop in AIDS
• Important part of mortality
• Increased incidence of all tumors
• Lymphoma of lymph nodes or GI tract
• Lymphoma of CNS: more common to see
lymphoma in the brain of HIV/AIDS patients than
those without.
• Lymphomas in AIDS patients are histologically the
same as other lymphomas
– Cytologically: they high grade, rapidly proliferating
• Very poor prognosis for patients with lymphoma
• Kaposi’s sarcoma
Karposi’s Sarcoma
•
•
•
•
•
Caused by herpes virus type 8
Not always AIDS related but AIDS related is more severe
Higher prevalence in homosexual male patients
Involves endothelial cells in skin and internal organs
Bluish red nodules filled with blood where blood vessels meet
or branch
– Skin: low back, mouth, face, genitalia
– Mouth: in AIDS patients, the palate of the mouth and gums, easily
break
– GI: silent lesions, weight loss, pain, n/v, diarrhea, bleeding,
malabsorption, obstruction
– Respiratory: SOB, cough, hemoptysis, chest pain,
• Nodules grow and eventually Leads to extensive bleeding and
death
AIDS Treatment
• No cure.
• Combination therapy works best.
– Highly active antiretroviral therapy
• May have to change regimen due to viral adaptation.
• Other medicines and vaccines will be used to prevent
opportunistic infections as needed.
• Vaccinations.
• Transmission prevention.
Individuals at Risk for
Immune Dysfunction
• Very young and very
old
• Poor nutrition
• Impaired skin integrity
• Circulatory issues
• Alterations in normal
flora due to antibiotic
therapy
• Chronic diseases,
especially diabetes
mellitus
• Corticosteroid therapy
• Chemotherapy
• Smoking
• Alcohol consumption
• Immunodeficiency
states
Immune-Building Strategies
• Increasing fluid intake
• Eating a well-balanced diet
• Increasing antioxidants and protein intake
• Getting adequate sleep
• Avoiding caffeine and refined sugar
• Spending time outdoors
• Reducing stress