Transcript Hypersensitivities, Infection and Immune Deficiencies

Chapter 7
Immune System
“protects against foreign antigens”
 Inappropriate
◦ Exaggerated – allergy
◦ Misdirected – autoimmunity
◦ Against beneficial foreign tissue –
alloimmunity
◦ Insufficient – immune deficiency
Hypersensitivity
 Allergy: exaggerated
◦ Deleterious effects of hypersensitivity
to environmental (exogenous) antigens

Autoimmunity: misdirected
◦ Disturbance in the immunologic
tolerance of self-antigens
(autoantibodies)

Alloimmunity: beneficial tissue
◦ Immune reaction to tissue of another
individual
Hypersensitivity
 Characterized by the immune
mechanism
◦ Type
◦ Type
◦ Type
◦ Type
I
II
III
IV
IgE mediated
Tissue-specific reaction
Immune-complex mediate
Cell mediated
◦ Tables:7-1, 7-2, 7-3
Mechanisms of Hypersensitivity
“require sensitization against Ag
from a 1° immune response”
“disease symptoms after 2°
immune response”
 Immediate – minutes to hours
◦ Anaphylaxis – rapid & severe
 Delayed
– hours to days
Type I Hypersensitivity
 IgE mediated
 Environmental antigens (allergens)
 IgE binds to Fc receptor on a mast
cell
 Histamine release
◦ H1 receptors
◦ antihistamines
Type I
 Genetic predisposition
 Tests
◦ Food
◦ Skin
◦ Lab (IqE)
 Desensitization
◦ IgG – blocking antibodies
Type II Hypersensitivity autoimmune
 Tissue specific
◦ Cells or tissue (tissue-specific
Ag) – target of an immune
response
Type II
 Five mechanisms
◦ Cellular destruction – Ab +
Complement
◦ Phagocytosis
◦ Neutrophil-mediated damage to
tissue
◦ Antibody dependent cell mediated
cytotoxicity (NK cells)
◦ Target cell malfunction
Type III Hypersensitivity
 Immune
complexes (Ag – Ab cplx)
◦ Formed in the circulation → vessel
walls or extravascular tissue → C3b
+ neutrophils → tissue damage
◦ SLE, serum sickness, Raynaud
phenomenon
Type IV Hypersensitivity
 Cytotic T-lymphocytes – lymphokine
◦ Direct killing or phagocytosis

Examples
◦ Acute graft rejection TB skin test,
contact allergic reactions (poison ivy)
◦ Type II collagen → rheumatoid arthritis
thyroid cell surface → Hashimoto
disease
◦ Pancreas → diabetes Type I
Allergy
 Environmental antigens that cause
atypical immunologic response –
genetically predisposed
individuals
◦ Pollens, molds, fungi, foods, animals,
dust
 Allergen
is contained within a
particle too large to be
phagocytosed or is protected by a
nonallagenic coat
Autoimmunity
 Loss of Tolerance
◦ Views self as foreign
 Examples
◦ Acute rheumatic fever – group A
streptococcal sore throat – M protein
– capsule mimics normal heart Ag →
antibodies to valve (Type II)
◦ Glomerulonephritis – bacterial Ag
into blood: immune cplx → kidney
(Type III)
Autoimmunity :Example
 Systemic lupus erythematosus
(SLE)
◦ “Chronic multisystem disease”
◦ Autoantibodies against
 Nucleic acids, erythrocytes, coagulation
proteins, phospholipids, lymphocytes,
platelets, etc.
◦ Deposition of immune complexes
 Kidneys, brain, heart, spleen, lung, GI
tract, peritoneum and skin
Alloimmunity
 Immune system reacts with
antigens on the tissue of other
genetically dissimilar members
of the same species
◦ ABO blood group
◦ Rh antigen
Alloimmune Disease
 Major histocompatibility complex
(HLA)
◦ Antigen – presenting molecules
◦ Chromosome #6 (A, B, C, DR, DQ & DP)




6 genetic loci
Class ICD8 on Tc cells
Class II
CD4 on Th cells
Class III
Complement
◦ More than 300 different HLA-A antigens
◦ Closer match with sibling
Graft Rejection
 Classified according to time
◦ Hyperacute
 Immediate and rare → white graft
 Preexisting antibody to the graft Ag (Type II
reaction)
◦ Acute
 Cell-mediated against unmatched HLA antigens
(days to months → Type IV reaction)
◦ Chronic
 Months to years, slow organ failure
 Weak cell mediated (Type IV reaction) –
endothelial cells of organ’s vessels
Infection
•
Number 1 cause of death world wide – 26%
2005
– Africa – 62% deaths
•
Developing countries – population & poor
sanitation
– Plague, cholera, malaria, tuberculosis, leprosy &
schistosomiasis
•
New disease
– West Nile virus, severe acute respiratory syndrome
(SARS), Lyme disease, Hantavirus and drug resistant
tuberculosis
 Exotoxin: protrin released during bacterial
growth
◦ Specific effects :cytotoxins, neurotoxins,
hemolysins…
◦ Immunogenic :
antibodies(antitoxins)
 Tetanus, diphtheria, pertussis
 Endotoxin: contained within the cell walls
of gram negative bacteria
lysis/destruction
◦ LPS: pyrogenic bacteria
DIC, shock
inflammation + fever,
Microorganisms and Human Relationships
• Mutual relationships
– Normal flora – Table 7-1
• Provided – nutrients
• Produce
–Enzymes to facilitate digestion
–Produce antibacterial factors #
colonization by pathogenic
microorganisms
–Useable metabolites (Vitamin K,
B)
•
Opportunistic organisms – immune
Table 7-1
Pathogenic Defense Mechanisms
• Surface coats
–Inhibit phagocytosis
•
Toxins
–Kill neutrophils & pyrogenic effect
•
Proliferation
–Rapid > immune response
•
Antigenic variation
–Mutation – antigenic drift
–Recombination – antigenic shift
–Gene switching
Bacteremia – Septicemia
 Presence
of bacteria in the blood
 Usually gram-negative bacteria
 Septic shock caused by
endotoxins
 Evaluation – blood culture
“bugs in da blood”
Institution: Zedek Medical Center, Jerusalem
Participants: 75 nurses, 60 physicians
Evaluation: Cultures of 3 spots on
uniforms
Findings: Potential pathogens on 63% of
uniforms.
Antibiotic resistant strains on 14%
nurses & 6% physicians.
Eight cultures grew MRSA
Suggestion: “infrequent hand washing”
Viral Disease
“most common affliction humans”
- colds → # cancers → AIDS
 Obligate intracellular parasites
◦ Dependent on the host cell
◦ No metabolism – incapable of
independent reproduction
◦ Permissive host cell
◦ Usually a self-limiting infection
 Spreads cell to cell
Viral Replication






DNA or RNA
Single or double stranded
Protein receptor – binding site
Virus uncoats
Most RNA viruses directly produce mRNA
DNA “provirus” enters nucleus and is
transcribed into mRNA
Viral Replication



Translation of mRNA results in the production
of viral proteins
New viruses are released through budding
Viral DNA, integrated into host cell DNA is
transmitted to daughter cells by mitosis.
Cellular Effects of Viruses
Inhibition of host cell DNA, RNA or protein
synthesis


Disruption of lysosomal membranes

Promotion of apoptosis

Fusion of infected, adjacent host cells

Alteration of antigenic properties
Cellular Effects of Viruses
 Transformation of host cell into cancerous
cells

Promotion of secondary bacterial infections
Clinical Manifestations of Infection

Variable depending on the pathogen
Direct cause → pathogen
Indirect cause → products
 Fever – “reset hypothalamus”
◦ Exogenous – cell walls - “LPS” → inflammation
◦ Endogenous IL-1, IL -6, interferon, TNF-a
Countermeasures
•
Vaccines
– “Induction of long-lasting protective immune
response – no disease in a healthy recipient →
memory cells (T or B):”
– Attenuated viruses (MMR, varicella)
– Killed organisms (hepatitis A)
– Recombinant viral protein (hepatitis B)
– Bacterial antigens – capsular polysaccharides
10 strains S. pneumoniae
– Toxins – diphtheria, cholera, tetanus → toxoid (IgG)
“chemical detoxified”
Countermeasures
 Antimicrobials:
◦ Inhibit synthesis of cell walls
◦ Damage cytoplasmic membranes
◦ Alter metabolism of nucleic acids
◦ Inhibit protein synthesis
◦ Modify energy metabolism
Pathogenic Adaptations

Immune system suppression
◦ HIV

Multiple drug resistance
◦ Streptococcal pneumonia,
tuberculosis, MRSA, VRE, E. coli,
Klebsiella
◦ Genetic mutation → selection
◦ “Overuse and compliance”
Immune Deficiencies :Lab Evaluation
Table 7-12

Hallmark
◦ Unusual or recurrent, severe
infections

Primary (congenital) immunodeficiency
◦ Genetic anomaly – single gene

Secondary (acquired) immunodeficiency
◦ 2° to another illness
◦ More common
Secondary (Acquired) Deficiencies
 Causes
◦
◦
◦
◦
◦
◦
◦
◦
Normal physiologic condition
Psychological stress
Dietary insufficiencies
Malignancy
Physical trauma
Medical treatment
Infection
AIDS
Where did the AIDS Virus arise?
 Evolved from a simian immunodeficiency
virus…chimpanzees

Southern and western Africa… 1931
◦ “Jumped species”

Spread slowly until mid-to-late 1950s
…when it spread exponentially
Acquired Immunodeficiency Syndrome (AIDS)
 RNA virus
◦ Depletes body’s Th cells (MHC II, CD4)
◦ Incidence
 40 million
 50,000 new/year USA (Denver Post: 8/11)-steady*
 18,000 RIP/year
◦ Chronic disease – HAART therapy

Epidemiology
◦ Blood-borne pathogen
◦ *Gay & bisexual men=2/3;heterosexual=1/4;IV
drug=1/10
AIDS
 Pathogenesis
◦ RNA virus
◦ Reverse transcriptase → RNA → double stranded
DNA
◦ Integrase – insertion of new DNA  into host DNA
AIDS
 Pathogenesis
 Th cells – “helpers”-CD4s
non-infected – 600 to 1200 mm3
infected - < 200 mm3 → AIDS
 Antibodies
 Blood product: 4-7 weeks
 Intercourse: 6-12 months
 Diagnosis: + serology + clinical
symptoms
AIDS
 Treatment
◦ HAART – highly active antiretroviral
therapy
 Inhibitor
 Reverse transcriptase
 Protease inhibitor

Vaccine
◦ Antigenically variable
◦ Ab – lack of protection