7 Flashcards
What are the 2 branches of adaptive immunity?
Humoral (B-cells) and Cell-mediated (T-cells - CD4, CD8)
Humoral immunity
Antibody production, Main defence against bacteria and bacterial toxins
Cell-mediated Immunity
Formation of a population of lymphocytes that attack and destroy infected cells (CD8), Main defense against viruses, fungi, parasites, cancers, and some bacteria, rejection of transplanted organs,
Chain of events when a foreign antigen enters the body
- Recognition of foreign antigen
- Proliferation of individual lymphocytes that are programmed to respond to the antigen form a large group (clone) of cells
- Destruction of pathogen /infected cells by the responding lymphocytes
T lymphocyte Response
Unable to respond to a foreign antigen (TCR) until a macrophage or dendritic cell (APC) cell has phagocytosed the antigen, digested it, and displayed on its cell membrane the antigen fragments combined with its own MHC proteins
B Lymphocyte Response to antigen
- Have immunoglobulin molecules (BCR) on their cell membranes that function as antigen receptors, and they can bind entire antigen molecules to their receptors (do not require MHC presentation)
- Processed into fragments
- Fragments displayed on the cell’s membrane with MHC class ll proteins for presentation and recognition by CD4 T-cells to enhance antibody production
Antibodies
Globulins produced by plasma cells and can only recreate to specific antigen that induce its formation
Antibody function
- Activation of complement
- Neutralization
- Agglutination
- Opsonization
Types of antibodies
- Immunoglobulin G (IgG)
- Immunoglobulin A (IgA)
- Immunoglobulin M (IgM)
- Immunoglobulin E (IgE)
- Immunoglobulin D (IgD)
IgG
- Smaller antibody
- Principal antibody molecule in response to majority of infectious agents
- Monomer shape
IgM
- Large antibody; a macroglobulin – early production before IgG is produced
- Responsible for immune control in early response
- Expressed on surface as monomer – secreted form (pentamer)
- Very efficient combining with fungi
- Pentamer
IgE
- Found in minute quantities in blood; binds to mast cells, basophils/eosinophils
- Concentration is increased in allergic individuals
- Important in controlling parasitic infections
- Monomer
IgA
- Produced by antibody-forming cells located in the respiratory and gastrointestinal mucosa (GI/respiratory and urogenital tract)
- Combines with harmful ingested or inhaled antigens, forming antigen–antibody complexes
- Dimer
IgD
- Found on cell membrane of B lymphocytes (Functions mainly as BCR) - no plasma cell
- Present in minute quantities in blood
- Monomer
What type of immunoglobulins are on Naïve B cells on their cell surface?
IgM and IgD
What do plasma cells do?
- Proliferation/Increased Ab production
- Class switching – specialized effector functions.
- Affinity Maturation – competition/ mutation
- Memory (travel to spleen/BM)
Why do B-cells need T-cells?
Ab production is weak and short lived with no memory
Methods of adaptive immunity control
- Cytokines (direct/control immune response)
- Tolerance (central/peripheral)
- Regulatory cells
- Activation vs. Anergy/Apoptosis
Loss of control of Adaptive Immunity
Hypersensitivity or Autoimmunity
Cytokine for cell-mediated immunity
IL-2
Cytokines for Humoral immunity
IL-4 and IL-5
IL-2
- Interleukin 2 is produced by T cells, It is the major growth factor for T cells. Also promotes the growth of B cells
- IL-2 acts on T cells in paracrine/autocrine fashion.
- Activation of T cells results in expression of IL-2R and the production of IL-2. promotes cell division.
IL-4
- Interleukin 4 is produced by macrophages and Th2 cells.
- stimulates the development of Th2 cells from naïve Th cells and it promotes the growth of differentiated Th2 cells resulting in the production of an antibody response.
IL-5
Interleukin 5 is produced by Th2 cells and it functions to promote the growth and differentiation of B cells and eosinophils. It also activates mature eosinophils.
TGF-Beta
- Transforming growth factor beta is produced by T cells and many other cell types. It is primarily an inhibitory cytokine.
- It inhibits the proliferation of T cells and the activation of macrophages. It also acts on cells to block the effects of pro-inflammatory cytokines.
INF-y
- Interferon gamma is an important cytokine produced by primarily by Th1 cells, although it can also be produced by Tc and NK cells to a lesser extent.
- It has numerous functions in both the innate and adaptive immune systems.
Th1 pathogens
- (cell based) geared towards viral/ bacterial attacks in blood/ tissues
- Polarize cells of adaptive and innate immunity to promote cellular immunity most effective against these invaders –PROINFLAMMATORY
Th2 pathogens
- (humoral-antibody) geared towards parasitic/mucosal infections.
- ANTIIFLAMMATORY
- Antibody based
- basis of hygiene
- Hypothesis, Allergy IgE
Cytokine Positive feedback
Th1/2 cytokines enhance and encourage Th1/2 functions and uncommitted cells (IL-2/IL-4)
Cytokine Negative feedback
Th1 inhibits Th2 functions and vice versa (IFNgamma/IL-10)
Central Tolerance
T and B cells must not react to self antigens and be restricted to self MHC molecules
Where do Immature T-cells go?
They go from bone marrow to the thymus from the blood
How do TCRs remain diverse?
They proliferate and rearrange gene segments
Positive selection - MHC
Cells that recognize MHC-peptide complexes receive rescue signals that prevent apoptosis
Negative Selection - self cells
Cells that survive positive selection exit the thymic cortex to the medulla where they are tested for tolerance to self-antigens
AIRE(autoimmune regulator) gene
Causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues
Fetal development
Full complement when born, activity of thymus decreases over time with large drop in thymic function after puberty
B-cells central tolerance
Decreased stringency of central tolerances mechanism compared to T-cells. B-cells continue to develop throughout life
Positive B-cell selection
Activate B-cell maturation
Negative B-Cell selection
Reaction to self
Peripheral Tolerance
Naïve T-cells stay in circulation, don’t stay in LN, or tissues so they only encounter a portion of the antigens in our body (compartmentalization)
Cell Anergy
Apoptosis; shut off the immune response (indirectly and directly)
Indirect cell anergy
Fewer antigens present to stimulate an immune response (DCs die after a few days, without continued support from macrophages and DC activated cells will doe off)
Direct anergy
Apoptosis and by molecular inhibition of immune functions (activated T cells are inherently pro apoptotic)
*Tim-3
*PD1/ PD1L
*CTLA-4
All deactivate the immune response
CTLA4-B7 binding
Makes less B7 molecules available for interaction with CD28; CTLA:B7 binding represses activation and block CD28 signalling (repression will shut down immune response)
What does the lack of co-receptor signals mean?
Anergy/death or compartmentalization
T reg cells
T cells that regulate activation of other T cells and necessary to maintain peripheral tolerance to self antigens; Produce cytokines that shut down the immune system
Natural T ref (nTreg)
Turn down immune response to self antigens
Inducible or adaptive Treg cells
Generated to self and foreign antigen after an inflammatory immune response
Hypersensitivity reactions
Allergy (Environment) and Autoimmunity (Self)
Types of hypersensitivity reactions
- Type I: Allergy (immediate)
- Type II: Cytotoxic
- Type III: Immune complex
- Type IV: Delayed hypersensitivity or cell-mediated hypersensitivity
Allergy response
IgE loading on mast cells, basophils, and eosinophils (mild reaction; rash, itching, swelling)
Allergy treatment
Environmental control, antihistamines, steroids, leukotriene inhibitors, allergen immunotherapy. Antihistamine drugs often relieve many allergic symptoms; histamine is one of the mediators released from IgE-coated cells
Anaphylaxis
Hypersensitivity reaction that may be life-threatening (fall in blood pressure and severe respiratory distress); Systemic response: peanuts, Bee sting, penicillin allergy
Require epinephrine to treat
Biphasic anaphylaxis reaction
Have a less severe initial reaction and 24hrs later have a much worse one
Atopic person
Allergy prone individual
Environmental susceptibility
Hygiene hypothesis (overly clean can make you more susceptible to illness)
Type 2: Cytotoxic
Antibody dependent (IgM, IgG) that combine with tissue or cell antigen creating lysis of cell or other membrane damage (examples: Autoimmune hemolytic anemia, blood transfusion reactions, Rh hemolytic disease, autoimmune glomerulonephritis)
Type 3: Immune complex
Ag-Ab immune complexes deposited in tissues activate complement pathway; Neutrophils attracted to site, causing tissue damage (examples: Rheumatoid arthritis, systemic lupus erythematosus (SLE), some types of glomerulonephritis)
Type 4: Cell-mediated, delayed hypersensitivity
Typically after 24-48 hours T lymphocytes are sensitized and activated on second contact with same antigen which induces inflammation and activates macrophages through lymphokines (Example: contact dermatitis, Diabetes Mellitus (T1), Rheumatoid arthritis)
Treatment for autoimmune disease
Various immune suppressing drugs/therapies (Corticosteroids, cytotoxic drugs, NSAIDS, immunotherapy with various biologics, antibody treatments (monoclonal – blocking or IVIG), symptomatic)
When can autoimmunity occur?
-Individual express MHC molecules that efficiently present self peptides (Two particular types of MHCII increase chance of type1 diabetes by 20 fold)
-Production of T and/or B cells that have receptors that recognize self (Random mix match, even identical twins will not share TCR repertoires (chance))
-Breakdown of tolerance mechanisms designed to eliminate these cells
Potential causes of Autoimmunity
*Defects in central tolerance deletion/ survival
*Defects in T Reg function/ numbers
*Defective apoptosis mechanisms (+ve/-ve)
*Inadequate inhibitory receptor functions (CTLA/ Fas)
*Chronic activation of APC’s, excessive T cell activation
Autoimmunity development
- Genetic susceptibility
- Failure of self tolerance/immune control
- Infection/ injury
- Activation of APC’s
- Recruitment of auto-reactive
lymphocytes - Activation of auto-reactive Lymphocytes
- Tissue injury from auto immune attacks
- Auto immune disease
Insulin dependent diabetes mellitus
Immune system targets insulin producing Beta cells in the pancreas (Islets of Langerhans) which is mediated by CTL activity, Dysfunctional natural Treg cells.
Myasthenia Gravis
Self reactive antibodies bind to acetylcholine receptors which results in muscle weakness and paralysis
Multiple Sclerosis
CNS inflammatory disease that is initiated by reactive T cells/ Macrophages causing chronic inflammation destroys myelin sheath protein, causing defect in sensory inputs
Rheumatoid Arthritis
Systemic autoimmune disease; Cartilage protein targeted causing chronic joint inflammation (IgM, IgG antibody complexes form in joints)
Lupus Erythematosus
Systemic: rash (forehead/ cheeks), inflammation of lungs, kidneys, joints, paralysis, convulsions; Breakdown in both T an B cell tolerance (lack of activation cell death may play a role)
Genetic mutations associated with Autoimmune disorders include dysregulation of
-Treg (FoxP3)
-Cell activation (IL-2, IL-12, CD2/58, Blk)
-Activation inhibitors (IL-10, CTLA4)
-Apoptosis (Bim, Fas)
-HLA alleles (MHC)
Which gender usually has an autoimmune disease
Women (80%), when makes get it they’re more severe
Autoimmune treatment
Symptomatic/ Immunosuppression Drugs:
-Corticosteroids/anti-inflammatory
-Chemical T cell/ B cell inhibitors/Cytokine blockers (IL-2)
-mAb to block immune receptors on T/B cells or cytokines (TNFa)
-Pain control/physical therapy
-IVIG – block Fc receptors on cells
Communicable disease
Disease transmitted from person to person
Endemic
Communicable diseases in which a small number of cases are continually present in the population
Epidemic
Communicable diseases concurrently affecting large numbers of people in a population (contained to a defined geographic area)
Pandemic
Global, world-wide outbreak across several countries or continents
Direct Transmission
Direct physical contact (sex) and Droplet spread (coughing, sneezing)
Indirect transmission through an intermediary mechanism
Contaminated food or water
Insects (vector)
Methods of Disease Control
Immunization (Active), Plasma containing antibodies/Maternal transmission (Passive), Identification, Isolation, treatment, controlling means of transmission (mask wearing), controlling indirect transmission for contaminated food or water
Isolation
Promptly carried out to shorten the time in which others may be infected, Isolation prevents contact with susceptible persons and stops spread
Food or water contamination control
Chlorination of water supplies, Effective sewage treatment facilities, Standards for handling, manufacturing, and distributing commercially prepared foods, Eradication and/or control of animal sources and vectors, Physical barriers - nets
Bubonic Plague
The black death has a 70% death rate without treatment, and 10% with treatment, one of the most deadly diseases, carried by rodents
STIs
Spread primarily by sexual contact (examples: Syphilis, Gonorrhea, Herpes, Chlamydia)
Primary Syphilis
Penetrates mucous membranes of the genital tract, oral cavity, rectal mucosa, or through the break in skin; multiplies rapidly throughout the body; forms a chancre (small ulcer) found on the penis, vulva, vagina, oral cavity, or rectum; occurs for 4-6 weeks and can heal without treatment
Secondary Syphilis
Systemic infection with skin rash and enlarged lymph nodes (develops after 4-10 wks typically lasts 2-3 years); begins after the chancre has healed and is accompanied with fever, lymphadenopathy, skin rash, shallow ulcers on mucous membranes of oral cavity and genital tract; can subside without treatment
Tertiary Syphilis
Late destructive lesions in internal organs (3-15y develops in 15-40% of cases); not generally communicable, Organisms remain active, causing irreparable organ damage due to chronic inflammation; Neuro and ocular syphilis are common in this stage
How to diagnose syphilis
Microscopic exam (Detection of Treponema from fluid squeezed from chancre) and Serologic tests (antigen–antibody reactions; Turns positive soon after chancre appears and remains positive for years)
Congenital Syphilis
Transmission from mother to child could cause the death of the fetus
When do gonorrhea symptoms occur?
A week later
Gonorrhea
Neisseria gonorrhoeae infection; Primarily infects mucosal surfaces: Urethra, genital tract, pharynx, rectum
Gonorrhea in females
Infects mucosa of the uterine cervix and urethral mucosa; profuse vaginal discharge from cervical infection; can be asymptomatic; Infection may spread to fallopian tubes (Salpingitis)
How does gonorrhea manifest
Abdominal pain and tenderness, Fever, Leukocytosis
Gonorrhea in males
Acute inflammation of the mucosa of anterior urethra, Purulent urethral discharge, Pain on urination, Less likely to be asymptomatic in males than females
Extragenital gonorrhea
In the rectum; Pain and tenderness; purulent bloody mucoid discharge (anal sex) or Pharynx and tonsils (Oral-genital sex acts)
Disseminated gonococcal infection
Organisms gain access to the bloodstream and spread throughout body; Fever; joint pain; multiple small skin abscesses; infections of the joints, tendons, heart valves, meninges
Diagnosis and treatment
Culture swab (Suspected sites: Urethra, cervix, rectum, pharynx, Blood in disseminated infections)
Nucleic acid amplification test: Based on the identification of nucleic acids in the organism
Treatment: Antibiotics - cefriaxone (some strains are penicillin resistant
Type 1 Herpes simplex virus infection
Infects oral mucous membrane and causes blisters; usually infected in childhood, most adults have antibodies to the virus; It may cause genital infections
Type 2 Herpes simplex virus infection
Infects genital tract and infections usually occur after puberty; Causes 80% of infections – a higher rate of recurrence, 20% of type 1 due to oral-genital sexual practices and may infect oropharyngeal mucous membranes
Herpes Manifestation
Vesicles (Small external painful blisters) and shallow ulcers following sexual exposure, Men (Glans or shaft of the penis), Women (Vulva - painful, Vagina or cervix - little discomfort)
Herpes diagnosis
Intranuclear inclusions in infected cells, Viral cultures from vesicles or ulcers most reliable diagnostic tests, and Serologic tests in some cases
Herpes Treatment
Antiviral drug shortens the course and reduces the severity, but does not eradicate the virus (orally, per IV, or topically), Cold compress and pain relievers, Deliveries should be done by cesarean section
Chlamydia trachomatis infection
Most common STD, 3 to 4 million cases per year
Chlamydia clinical manifestations
Similar to gonorrhea (infection can spread to fallopian tubes to have similar effects), many are asymptomatic
Chlamydia in Women
Cervicitis and urethritis, involving the uterine cervix, and urethra; moderate vaginal discharge (Major complications: sterility)
Chlamydia in Men
Nongonococcal urethritis, acute urethral inflammation with frequency and burning on urination (Major complications: epididymitis)
Chlamydia Diagnosis
Detection of chlamydial antigens in cervical or urethral secretions, Fluorescence microscopy
Cultures (swabs), Nucleic acid amplification tests: based on chlamydial nucleic acids
Chlamydia Treatment
Antibiotics (azithromycin/doxycycline)
Condylomata
Anal and genital warts - HPV
Trichomonal vaginitis
Trichomonas vaginalis infection (protozoan parasite)
Scabies and crabs
Microscopic mites
HIV Virus
Attacks the immune system, specifically destroying CD4 T cells, leads to the development of Acquired Immuno Deficiency Syndrome which increases susceptibility to pathogens and opportunistic infections.
Genetic material and Proteins in the HIV virus
9 kb Genome, ssRNA retrovirus (+ve), codes for 9 proteins, 2 structural proteins (Gag and Env), 1 enzymatic protein (Pol), 6 regulatory proteins (Tat, Rev, Nef, Vif, Vpr, and Vpu)
HIV Transmission
Sexual contact, Blood and body fluids (seminal, vaginal), Mother to infant (HIV primarily infects CD4 T-cells through interactions with CD4 receptors on the cell surface and GP120 spikes on virus
HIV Direct inoculation
Intimate sexual contact, linked to mucosal trauma from rectal intercourse
HIV Transfusion
Contaminated blood or blood products, lessened by routine testing of all blood products, Sharing of contaminated injection needles, Transplacental or postpartum transmission via cervical or blood contact at delivery and in breast milk
HIV steps of infection
- HIV cannot multiply alone. It must be inside a cell before it can make copies of itself.
- When HIV infects a cell, it hijacks its machinery.
- In the host cell, HIV makes copies of itself.
- These newly created virus particles can then go infect other cells.
HIV life cycle
Binds to CD4 and enters the cell, reverse transcriptase converts RNA into DNA (errors and mutations occur in this step), DNA is then transported into the nucleus, intergrase integrates the viral DNA into the host cell’s genome (can be inactive), once activated genes are transcribed and viral RNA is transported to the cytoplasm, proteins are translated and cleaved by a protease, virions are released at the membrane, T-cells are activated and support the infection
HIV replication and Genetic Variability
Fast replication and high mutation rate (1/cycle). This provides an adaptive advantage to HIV
What mutants are immune to infection with HIV?
CCR5 (highly expressed in macrophages)
CD4 T-cells abnormalities
Depletion/cell death, reduced proliferation /regeneration, destruction by infection, indirect and direct destruction by viral proteins
HIV to AIDS
A healthy individual has between 800 and 1500 CD4T cells in 1 µL of blood. Immune deficits start to emerge below 500 (HIV/other autoimmune diseases), Once this number drops below 200, the individual is described as having AIDS.
Cytopathic effects of HIV
Cell-cell fusion, accumulation of unintegrated viral DNA, alteration of cell permeability lipids, apoptosis, the release of toxic cytokines by infected cells, destruction of immune responses, inhibition of growth factors, degradation of RNA which reduces protein synthesis
CD8 T-cells are destroyers using…)
Cell-to-cell contact and secreted factors destroy infected cells (Perforin/Granzyme A, B) and inhibit virus production/promote immune activation (IFNy, TNFa, IL-2, MIP1a/b, RANTES)
What is CTL dysfunction caused by?
Cytokine/ receptor dysregulation, Direct effect of HIV soluble factors, Cell death/ apoptosis, Other immune cell dysfunction, Anergy
What is Anti-HIV CTL (CD8) activity associated with?
LTNP/Elite controllers (some control of the HIV infection and slower disease progression)
Early vs. Late Manifestations of HIV infection
Early (Asymptomatic, mild febrile illness) and Late (Generalized lymph node enlargement, nonspecific symptoms, fever, weakness, chronic fatigue, weight loss, thrombocytopenia, AIDS)
Antibody response to HIV
Antibodies are formed within 1 to 6 months, Detection of antibodies provides evidence of HIV infection, Antibodies do not eradicate virus, Virus is detectable by laboratory tests (viral RNA)
Signs and Symptoms of AIDS
An infected person usually experiences a mononucleosis-like syndrome that may be attributed to the flu or another virus (may be asymptomatic for years)
Non-specific symptoms of AIDS
Weight loss, fatigue, night sweats, and fever
Viral replication
Measure the amount of viral RNA in the blood (Virus replicates in lymph nodes, but the amount of viral RNA in blood reflects extent of viral replication in lymphoid tissue)
Treatment for HIV and AIDS
No cure for AIDS, antiretroviral agents inhibit HIV viral replication
HIV Treatment groups
Nonnucleoside reverse transcriptase inhibitors, Nucleoside reverse transcriptase inhibitors (nucleoside analogs), Protease inhibitors, Integrase inhibitors
Protease Inhibitors
Block the action of viral protease in viral replication; cut viral protein into short segments to assemble around viral RNA to form infectious particles
PrEP
HIV prevention treatment
Pathogenic Organism types
Bacteria, Viruses, Fungi
Bacteria types
Chlamydiae, Rickettsiae and Ehrlichiae, and Mycoplasma
Classification of Bacteria
- Shape and arrangement(coccus, bacillus, spiral), Gram strain reaction (Gram-positive and Gram-negative)
- Biochemical and growth characteristics (Aerobic and anaerobic, spore formation, and biochemical profile)
- Antigenic structure (antigens in the cell body, capsule, flagella (motility)
Bacteria Genomic Sequence
16S ribosomal RNA, proteins and peptides are seen
Coccus (Spherical) Bacteria
Clusters: Staphylococci
Chains: Streptococci
Pairs: Diplococci
Kidney bean-shaped (in pairs: Neisseriae)
Bacillus (rod-shaped) Bacteria
Square ends: Bacillus anthracis (anthrax)
Rounded ends: Mycobacterium tuberculosis (TB)
Club shaped: Corynebacterium (Diptheria)
Comma shaped: Vibrio (Cholera)
Spiral Organisms
Tightly coiled: Treponema pallidum (Syphilis)
Relaxed coil: Borrelia (Lyme)
Steps of Gram-Staining
Step 1: Crystal violet (purple dye) – stains peptidoglycan
Step 2: Gram iodine (acts as a mordant)
Step 3: Alcohol or acetone (rapid decolorization)
Step 4: Safranin (red dye)
How do gram positives stain?
Resists decolorization and retains the purple stain (cell wall is composed of multiple peptidoglycan layers combined with teichoic acid; lipopolysaccharide absent)
How do gram negatives stain?
Can be decolorized and stained red (the cell wall is composed of a thin peptidoglycan layer and lacks teichoic acid; lipopolysaccharide present)
True or False: All bacteria can be stained
False; Mycobacterium has no cell wall and is unable to be stained
Cocci Gram-Positive
Staphylococci, Streptococci, Pneumococci
Cocci Gram-Negative
Gonococci and Meningococci
Bacilli Gram-Positive
Corynebacteria, Listeria, Bacilli, Clostridia (Oxygen and spore forming)
Bacilli Gram-Negative
Haemophilus, Gardnerella, Francisella, Yersinia, Brucella, Legionella, Salmonella, Shigella, Campylobacter, Cholera bacillus, Colon bacillus (E. coli + related organism)
Spiral organisms (Gram-Negative only)
Treponema pallidum and Borrelia burgdorferi
Acid-fast organisms (Gram-Positive only)
Tubercle bacillus and Leprosy bacillus
Staphylococci
Gram-positive cocci in Grapelike clusters found in the skin (epidermis) or the nasal cavity (aureus); normally not pathogenic but opportunistic
Staphylococci pathogenic strains cause
Vomiting and diarrhea, toxic necrosis, tissue necrosis, hemolysis, inflammation (distinguished by culture on blood agar plates)
Staphylococci Infections
Impetigo, boils, nail infection, cellulitis, surgical wound infection, eye infection, postpartum breast infections, Abscess
A drug-resistant strain of Staphylococci
Methicillin-resistant Staphylococcus aureus, or MRSA (antibiotic-resistant)
Streptococci are found…
Gram-positive cocci arranged in chains or pairs, normal inhabitants of skin, mouth, pharynx (Streptococcus viridans), gut, female genital tract (peptostreptococci); opportunistic organisms
Streptococci Diseases
3 types: pyogenic, toxigenic, and immunologic
Pyogenic Streptococci Diseases
Pharyngitis, cellulitis, endocarditis, urinary tract infection
Toxigenic Streptococci Diseases
Scarlet fever, toxic shock syndrome
Immunologic Streptococci Diseases
Rheumatic fever, glomerulonephritis (induce hypersensitivity)
Streptococci Classification
Lancefield classification groups A to V (Most significant: A, B, D)
Group A Streptococci
Many pathogenic strains (Streptococcus pyogenes): cause pharyngitis, strep throat, tissue infections (necrotizing fasciitis, gangrene)
Group B Streptococci
(Streptococcus agalactiae): Anal/Genital tract of women, neonatal transmission risk, meningitis, sepsis
Group D Streptococci
Enterococcus faecalis, Streptococcus bovis): Urinary, biliary, and cardiovascular infections – difficult to treat and Ab resistant
Beta hemolysis
Complete lysis of red cells
Non-beta hemolysis (2 types)
Alpha hemolysis: Incomplete lysis of red cells (Streptococcus pneumoniae, Strep mutans (tooth decay)
Gamma hemolysis: Nonhemolytic, no lysis
Non-pathogenic Gram-positive bacilli
Corynebacteria are found in the skin except for C. diphtheria (Ulcers in the throat and injured heart + nerve tissue)
Listeria monocytogenes (a food contaminant found in nature - can cause systemic illness leading to meningitis)
Pathogenic Gram-positive bacilli
Bacillus anthracis (Anthrax); Spores are spread through inhalation (can remain as spores) and spread rapidly in alveoli, germinate in the lymph nodes, and produce toxins (fever, chest pain, 20% fatality without treatment in days)
Bacillus anthracis (Anthrax) Treatment
Requires long courses AB treatment
Gas gangerne (Clostridium perfringens)
Contaminate wounds, proliferate in dead/necrotic muscle tissue (ferment necrotic tissue), releasing tissue-destroying toxins with systemic effects (sepsis). Toxins also cause neutrophil lysis
Tetanus (C. Tetani)
Produces neurotoxin that causes sustained muscular contractions (bone fractures), Symptoms days to weeks after exposure, Fatal due to effect on respiratory muscles
Botulism (C. botulinum)
Food poisoning from toxin ingestion of improperly cooked/ stored food, infants particularly susceptible, produces neuroparalytic toxins – pathology not caused by infection
Intestinal infection (C. Diff)
Hard to get rid of due to antibiotic resistance (broad spectrum Ab use)
Hemophilus Influenzae
Gram -ve; Variety of infections lung, CNS, Skin, blood
Yersinia pestis
Gram -ve; Plague
Salmonella, Shigella, Campylobacter
Gram -ve; Food poisoning - GI infection
Legionella (Legionnaire’s disease)
Gram -ve; severe pneumonia
Vibrio Cholerae (Cholera)
Gram -ve; severe, acute watery diarrhea
Helicobacter pylori
Gram -ve; stomach inflammation - Ulcers
E.coli
Gram -ve; Common to GI tract residents but some strains that are ingested by raw/uncooked animal products (typically can develop toxic effects including inflammation, anemia, bloody diarrhea and abdominal pain.
Spiral organisms diseases
Syphilis (Tremponema pallidium), Lyme disease, Acid-fast bacteria, and Leprosy
Lyme disease (Borrelia burgdorferi) + how does it spread?
Transmitted though infected tick bite to spread throughout the body
3 stages:
Stage 1: circular “bulls eye” rash accompanied with flu like symptoms
Stage 2: cardio (heart palpitations), neuro (meningitis, facial paralysis) and joint pain
Stage 3: chronic arthritis and neuro deficits (memory, fatigue, insomnia)
Acid-fast bacteria
Hard to stain due to waxy coat; causes granulatomas inflammation (Macrophage infection) and TB (Mycobacterium tuberculosis) which primarily infects lungs
Leprosy (Mycobaterium leprae)
The infection leads to skin lesions, peripheral nerve damage (lack of sensation, muscle weakness, vision loss); low infectivity and pathogenicity; inflammation of Schwann cells causes most of the damage
Chlamydiae
Gram-negative, nonmotile bacteria, obligate intracellular parasites, rigid cell wall, no vaccine available for treatment
Chlamydial Diseases
Psittacosis (pneumonia): Inhalation of dried bird feces
Trachoma (Chlamydia trachomatis A, B, C): Chronic conjunctivitis, blindness
Nongonococcal urethritis (men): Spread to other areas
Cervicitis (women): Lead to salpingitis, pelvic inflammatory disease, infertility, ectopic pregnancy
Neonatal inclusion conjunctivitis: Newborn from infected mother
Rickettsiae and Ehrlichiae
Obligate intracellular parasites (typically endothelial cells)– both transmitted by insect bites and respond to some antibiotics
Rickettsia Disease
Infects, proliferates endothelial cells in small blood vessels of skin - causing damage, leakage of blood into surrounding tissues (rash and edema)
Rocky Mountain Spotted Fever (ticks)
East Coast spring and early summer; flu-like and Rash after 2 to 6 days on hands and feet then the trunk, affects CNS
Rickettsialpox (mites from mice) symptoms
flu like symptoms, full-body rash
Typhus symptoms and illnesses
Flu-like, rash (epidemic: lice; endemic: fleas, mites)
Ehrlichiosis Transmission and Symptoms
Transmitted via the bite of an arthropod vector (ticks, mites, lice, fleas), Infect and multiply in neutrophils or monocytes, Cause febrile flu-like (muscle aches, chills) illness with skin rash, Transmission enhanced by poor hygiene, overcrowding, wars, poverty
Primary atypical pneumonia (+Symptoms and treatment)
Mycoplasma pneumoniae; Most common in winter, young adults, outbreaks in groups; Cough, sore throat, fever, headache, malaise, myalgia, Resolves spontaneously in 10 to 14 days and responds to antibiotics: Tetracycline and erythromycin
Viruses’ Nucleic acid structure
Either DNA or RNA (ss,ds, +/-ve), enclosed in a capsid, with an outer envelope made of lipoprotein (often from host cell)
Virus size
Smaller than cells (20 to 300 nm diameter) and cannot be seen under a light microscope
Nucleoid
Genetic material, DNA or RNA, not both (centre of virus)
Capsid
Protective protein membrane surrounding genetic material in virus
Coat/Envelope
Surrounds the virus (combination of host membrane and viral proteins (retrovirus)) - non-enveloped viruses, adenovirus, exist
True or False: Viruses lack metabolic enzymes
True, they rely on the host’s metabolic processes for survival
HIV
destruction of the immune system
HPV
proliferation and neoplasia
Ebola
acute cell necrosis and degeneration
HCV
slowly progressive cell injury
HSV, VZV: Herpes Zoster/Shingles
Invades a susceptible cell, Asymptomatic latent viral infection
Modes of action in various viruses
Invades a susceptible cell, Asymptomatic latent viral infection (HSV, VZV: Herpes Zoster/Shingles) – dormant in neural cells
Acute cell necrosis and degeneration (Ebola)
Cell hyperplasia
Proliferation and Neoplasia(HPV)
Slowly progressive cell injury (HCV)
Destruction of the immune system (HIV)
Bodily defences against viral infections
(Innate/Adaptive) formation of interferons: Broad-spectrum antiviral agent inhibits viral replication (non-specific), activates immune cells
- Cell-mediated Immunity
- Humoral defences
What do anti-viral agents do?
Block viral replication (HIV/HCV), prevent the virus from invading cells (HIV) - the best defence is a vaccination for community and personal immunity
Fungi
Plantlike organisms without chlorophyll, are obligate aerobes
Types of Fungi
Yeast (small ovoid/spherical), mold - spoilage of foods (branching/filamentous), Bread, cheese, wine, and beer production
Fungi cell wall vs. bacteria cell wall
Chitin vs. peptidoglycan
Fungi vs. bacteria cell membrane
Erogosterol and zymosterol vs. cholesterol
Fungi growth factors
High humidity (moist), heat, dark areas with oxygen supply
How can Fungi cause disease
Present in natural habitat and can cause chronic disease, become opportunistic in immunocompromised, lose regular flora due to antibiotics, cause superficial skin infections
Fungi treatment
Antifungal drugs or topical treatment in mild cases
Mucous membranes (Candida albicans)
Common in immunocompromised patients with
fungal infection on tongue, mouth, esophagus (thrush)
Aspergillus fumigatus
Spores from decaying plant matter can result in severe pulmonary and systemic disease in immunocompromised, asthma can develop
Histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis
Inhaled spores from dust; usually acute, self limited respiratory infection, involve blood vessels in severe cases (systemic disease)
Antibiotics mechanism
Inhibits synthesis of the bacterial cell wall (leads to swelling-rupture), inhibits bacterial metabolic functions, and cell membrane(injury-death)
Penicillin family
Penicillin, methicillin, nafcillin, oxacillin, amoxicillin, ampicillin, piperacillin, ticarcillin
Cephalosporins
Cephalexin, cefoxitin, ceftazidime, ceftriaxone; vancomycin, bacitracin
Chloramphenicol
Tetracycline; macrolide; erythromycin, azithromycin, clarithromycin; clindamycin, gentamicin, netilmicin, streptomycin
Antibodies that inhibit bacterial DNA synthesis
Ciprofloxacin, norfloxacin, ofloxacin
Antibiotic Sensitivity Tests: Tube dilution
Measures the highest dilution that inhibits growth in test tube
Antibiotic Sensitivity Tests: Disk method
Inhibition of growth around the disk indicates sensitivity to antibiotic
Antibiotic Sensitivity Tests: MALDI-TOF-MS
Identification of strains with known antibiotic-resistance characteristics
What do tetracycline levels test?
Kidney Function
Adverse effects antibiotics
Toxicity, hypersensitivity (allergy), alteration of normal bacterial flora (resistance)
Development of resistant bacteria
Spontaneous mutation and Plasmid-acquired resistance
Mechanisms for circumventing effects of antibiotics
Develop antibiotic enzymes (penicillinase), Change cell wall structure (repel Ab), and change internal metabolic machinery (Ab loses function/binding)
Cause of antibiotic resistance
Over-prescribing of antibiotics, patients not finishing their treatment, poor infection control in hospitals and clinics, over-use of antibiotics in livestock and fish farming, lack of hygiene and poor sanitation, lack of new antibiotics being developed
Mechanisms of control for cell growth
Constant renewal (Hair follicles, gut lining), Stable, but can renew when stimulated (T-cells), Permanent, therefore, no renewal (cardiac muscle)
How is cancer developed?
Loss of control of cell division/ mutation of a gene
Characterization of Cancer tumours
Benign vs. Malignant
Solid vs. Invasive
In situ vs. Infiltrating
Benign Tumor characteristics (Growth rate, Character of growth, Tumor spread, Cell differentiation)
Growth rate: Slow
Character of growth: Expansion
Tumor spread: Localized (Brain tumors can do damage while being benign)
Cell differentiation: Well differentiated
Malignant Tumor characteristics (Growth rate, Character of growth, Tumor spread, Cell differentiation)
Growth rate: Fast
Character of growth: Infiltration
Tumor spread: Metastasis by bloodstream and lymphatics (establish secondary sites)
Cell differentiation: Poorly differentiated
Benign tumor classification
The cell of origin (Prefix-) and -oma (suffix)
Malignant tumor classification
3 groups (carcinoma, sarcoma, leukemia/lymphoma)
Carcinoma cancer
Most common (85% of tumors); Epithelial tissue (arises from the surface, glandular or parenchymal epithelium) and spreads through lymph nodes
Adenocarcinoma
Subtype of carcinoma cancer (ex. pancreas - glandular/ secretory cells)
Squamous cell carcinoma
Subtype of carcinoma cancer found on skin
Sarcoma cancer
Less common; Arise from connective tissue, endothelium, and mesothelium and spreads rapidly through the bloodstream
Fibrosarcoma
A subtype of sarcoma cancer affects fibroblasts
Myosarcoma
A subtype of sarcoma cancer affects muscles
Leukemia
Neoplasm of blood cells; non-solid tumors and overgrows and crowds out normal blood-forming cells
What happens if neoplasm cells populate LN and spleen
Lymphoma (T cell/ B cell)
Neoplasm development
A stepwise process that involves ongoing series of genetic changes over time (activation of oncogenes, loss of function of one or more tumor suppressor genes, and additional random genetic changes)
What does cancer in stem cells cause?
A tumor with a high degree of heterogeneity
True or False: Fast-growing neoplasms may outgrow the blood supply
True, this can be used as a therapeutic target
True or False: Tumors have their own blood supply
False, tumors derive blood supply from tissues they invade
Angiogenesis
Malignant tumors frequently induce new blood vessels to proliferate in adjacent normal tissues to supply the demands of the growing tumor
Necrosis in parts of malignant tumors
When the tumor outgrows its blood supply part with the poorest blood supply undergoes necrosis
The blood supply in tumors in the lung
Blood supply is best at the periphery of the tumor and poorest at the center (central necrosis)
The blood supply in tumors growing outward from an epithelial surface (ex. colon)
The best blood supply is at the base and the poorest at the surface (peripheral necrosis)
How can genetic change occur in cancer-causing genes?
Radiation, carcinogens, viruses – failure of DNA repair/fidelity mechanisms, Failure of Immune defences, over time these can accumulate (age-dependent), can also be inherited susceptibilities to developing cancer
Proto-oncogene
Philadelphia chromosome – seen in chronic granulocytic leukemia (translocation of pieces of chromosome 9 and 22); a very aggressive cancer
Loss of apoptotic control leads to…
Uncontrolled cell growth and cells eventually form a tumor
Tumor-suppressor genes
Genes (expressed in pair of homologous chromosomes) that inhibit/control cellular division/proliferation; prevent DNA replication (ex. APC, DCC, p53)
What virus causes leukemia and lymphoma?
T cell leukemia–lymphoma virus (HTLV-1) that is related to the AIDS virus (tax onocogene)
What virus causes Kaposi sarcoma?
Human herpesvirus 8 (HHV-8)
What virus causes Condylomas (warts)
Papilloma virus (HPV); predisposes to cervical carcinoma
What virus causes Chronic viral hepatitis
Hepatitis B and C viruses (chronic inflammation/repair)
What virus causes Nasopharyngeal carcinoma
Epstein-Barr virus also causes infectious mononucleosis
Which immune cells detect and destroy cancerous cells?
CD8 T-cells and NK cells
Which cancers do those with severe immunodeficiency have an increased risk of?
Blood and skin cancers
True or False: All mutations that cause cancers are directly related
False, Most mutations that cause cancer are not directly inherited (it can influence it, ex. only 10% of breast cancer cases linked to genetic mutations)
Which abnormal gene causes an 80% risk of breast cancer by age 90
BRCA1/2 DNA repair genes
Neurofibromatosis
increased production of benign tumours of the nerves that have an increased risk of malignancy (autosomal dominant)
Actinic keratoses
Small, crusted, scaly patches that develop on sun-exposed skin; may develop into cancer if untreated
Lentigo maligna
The freckle-like proliferation of melanin-producing cells that may develop on sun-exposed skin; may transform into melanoma
Leukoplakia
Thick white patches in the mucous membranes of the mouth from exposure to tobacco tars from pipe or cigar smoking or smokeless tobacco (may give rise to squamous cell cancers of the oral cavity)
Diagnosis of Tumors
Recognize early warning signs and symptoms, Complete medical history and physical examination, screening early (need to consider invasiveness/severity, cost/benefits), Surface – Visual, Orifice (opening) – Endoscopy, Internal – CT scan/MRI, Lab procedures
Cytologic diagnosis
Fine needle aspiration, biopsy (many organs – precise location of tumor by CT, Xray or US)
Histology
Frozen section Slides prepared and stained – rapid histological diagnosis in minutes
Abnormal smear
Slides of abnormal cells shed from surface of tumors
Tumor-associated antigen tests
Some cancers secrete substances that can be detected in the blood by lab tests (Carcinonembryoic antigen, Alpha-fetoprotein, Human chorionic gonadotropin, Acid phosphatase)
Carcinoembryonic antigen (CEA)
Produced by most malignant tumors of the GI tract, pancreas, breast
Alpha-fetoprotein
Normally produced by fetal tissues in the placenta but not adult cells
Human chorionic gonadotropin
Normally produced by the placenta in pregnancy
(PSA test) Acid phosphatase
Normally produced by prostate epithelial cells
Treatments of tumor
Surgery, TNM Classification, Staging I-IV, Radiotherapy, Hormones (Corticosteroids), Chemotherapy (anti-cancer drugs), Adjuvant chemotherapy,
TNM Classification
T- size 1-4, N spread to regional LN 1-3, M distant metastasis 0-2
Staging I-IV
Early, localized, regional spread, distant spread
Chemotherapy
Lasts 3-6 months (4-8 cycles of 3-4 weeks), 3 stages: Induction (1 month intensive) /Consolidation (few months) / Maintenance (2-3 years); Normal cells recover quickly, side effects disappear gradually (prognosis of the patient depends on their overall health and the type of anticancer drugs used)
Alkylating agents
Inhibit DNA synthesis, structure or function (DNA replication)
Side effects of chemotherapy
Anemia, Constipation, Depression, Diarrhea, Hair loss (alopecia), Infection, Loss of appetite (anorexia), nausea and vomiting, Mouth, gum, and throat problems; sores, and sexual problems
External Radiation Therapy
Damages DNA to disrupt growth of cancer, targeted external bean for 15 min 5x/week for 3-9 weeks
Internal Radiation Therapy
Tablet, liquid (IV) or brachytherapy (implant to deliver radioactive dose directly to tumor); fewer side effects compared to external
Considerations for Surgery (PROO)
Patient health/survivability (risks)
Resectability of tumor
Operability of tumor
Other treatment options
Immune system cancer control (CNMA)
CD8 (Cytotoxic) T cells destroy cancer antigens presented by MHC I
NK cells can destroy cells expressing stress signals, deficient MHC I expression
Macrophages can destroy tumor cells by phagocytosis
Antibodies to tumor antigens can tag tumor cells for destruction by Macrophages/ complement
Immunotherapy (Non-specific or Specific types)
Stimulating the body’s immune response to attack cancer
Nonspecific: Cytokines
Specific: Tumor-infiltrating lymphocyte therapy, Tumor vaccines, Tumor antibody therapy
IFN alpha
Has general antiviral effects, inhibition of tumor growth, useful in leukemia, multiple myeloma
IL-2
Stimulates NK cells and Cytotoxic CD8 T cells
and used in metastatic melanoma, renal cell carcinoma
CAR-T therapy
Specific Immunotherapy; Genetic TCR alteration
Dendritic cell therapy
Activation of dendritic cells in presence of tumor antigens
Anti-tumor vaccines
Tumor antigens from patient used to immunize patient against recurring disease after resection
Anti-tumor antibodies
Specific antibodies directed against tumor, sometimes linked with antitumor drug (chemo) or toxin (radioactive)
Drugs to remove blockades that are inhibiting immune function
Prevents tumor immune suppression functions (CTLA-, PD1, PD-L1)
Oncolytic viruses (Vaccinia, Vesicular stomatitis virus)
Infects and kills cancer cells, stimulate anti-tumor immunity - Attenuation
Thyroid cancer survival rate
95% (5-year rate)
Pancreatic cancer survival rate
4% (5-year rate)
Most common cancers in males and females
Lung cancer (males) and Breast cancer (females)
Plasma
Fluid component of blood
Blood composition and function
Red cells, leukocytes, and platelets; carries antibodies, oxygen, nutrients, hormone , and CO2 plus other waste products
Red blood cell function
Oxygen/Carbon Dioxide exchange
(the more red blood cells the more oxygen you can carry); Most numerous cells in the blood
Leukocytes (WBC) function and types
Immune functions; Neutrophils (Most numerous – first line), Monocytes (Phagocytic Macrophages), Eosinophils (Allergy, parasitic infections), Lymphocytes (Adaptive Immunity), and Basophils (Parasitic infections)
Platelet function
Hemostasis
Stem cells
Precursor cells in bone marrow that differentiate to form red cells, white cells, and platelets (any cell) - Hematopoietic stem cells differentiate into any blood cell type
Erythroblast
Precursor cells in bone marrow
Hemoglobin
An oxygen-carrying protein formed by the developing red cell
Ganulocytes/ Polymorphpnucleargraulocytes
PMN - Eosinophils, Basophils, Neutrophils
Where are Lymphocytes produced?
Mainly in lymph nodes and spleen; some are produced in bone marrow
Neutrophils
The first line of defence (Most numerous in adults,
Makeup 60-70% of total circulating WBC, Actively phagocytic, Predominant in inflammatory reactions)
Monocytes
3-5% of leukocytes (Increased in certain types of chronic infection, Circulate to sites of inflammation, Transition to Macrophages (APC), Infection/tissue repair)
Eosinophils/Basophils
Present in low numbers (Increased in allergic reactions and Increased in presence of animal–parasite infections)
Lymphocytes
15-20% of leukocytes (T/B cells, seen predominantly in children, Mostly located in lymph nodes, spleen, and lymphoid tissues (some in circulation plus lymphatic system), cell-mediated and humoral defence reactions)
Platelets
Essential for blood coagulation, Much smaller than leukocytes, Represent bits of the cytoplasm of megakaryocytes, the largest precursor cells in bone marrow, Short survival, about 10 days
Hematopoiesis
Formation and development of blood cells; bone marrow replenishes blood cells (damage/age)
Substances necessary for hematopoiesis
Protein, Folic Acid, Vitamin B12 (required for DNA synthesis), Iron (Decreased RBC production if any of these are lacking)
How is RBC production regulated
Oxygen content in blood which stimulates hormone (epo) release from kidneys
True or False: High reticulocyte count indicates the body is creating a lot of RBC
True, they leave bone marrow and differentiate into RBC in circulation
Red cell production
Regulated by oxygen content of the arterial blood – stimulated by erythropoietin
White cell production
Regulated by Interleukin levels/ response to infection – complex
Hemoglobin
96% of RBC content Tetramer is composed of four subunits, each one consisting of heme and globin
Heme
Porphyrin ring that contains an iron atom
Globin
The largest part of hemoglobin; forms different chains designated by Greek letters such as alpha, beta, gamma, delta, and epsilon
Porphyrin ring
Produced by the mitochondria; iron is inserted to form heme
Reticulocyte
A young red cell without a nucleus, but retains some organelles; identified by special strains found in bone marrow (matures in 24-48)
Globin chains
Produced by ribosomes; joined to heme to form a hemoglobin unit (4 subunits to complete hemoglobin tetramer)
Red blood cell degradation
Worn-out red cells are removed in the spleen, Hemoglobin is degraded and excreted as bile by the liver, The porphyrin ring cannot be salvaged, Globin chains break down and are used to make other proteins, and Iron is extracted and saved to make new hemoglobin
Reduced oxygen supply stimulates
Erythropoiesis (erythropoietin)
High partial pressure oxygen in lungs
Promotes binding
Low partial pressure oxygen in tissues
Promotes release
Methemoglobin Iron
Fe 3+, not in ferrous state, can’t bind oxygen, inherited disorder or response to toxic agents
Carboxyhemoglobin
Binds CO with high affinity (200x stronger than oxygen), blocks oxygen binding, products of incomplete combustion
Where are Iron reserves stored?
Liver, bone marrow, and spleen
What do Duodenal cells produce?
Hepcidin to block uptake by duodenal cells and interferes with iron transport
Hemochromatosis
Common genetic disease transmitted as an autosomal recessive trait – chronically absorbs too much iron
Reasons for Iron overload
Patients who take iron supplements chronically, or have blood disorders where there is a loss of RBC destruction (sickle cell), overload due to inability to reduce iron levels
Treatment for Hemochromatosis
Periodic removal of blood (phlebotomy) until iron stores are depleted, and use of iron chelation treatment to remove iron
Anemia causes
Insufficient raw materials (Iron deficiency, vitamin B12 deficiency, Folic acid deficiency), Inability to deliver adequate red cells into circulation due to marrow damage or destruction (aplastic anemia), excessive loss of red cells
Hemorrhage
External blood loss
Sickle cell, thalassemia
Shortened survival of red cells in circulation
Hereditary hemolytic anemia
Defective red cells
Normocytic anemia
Normal size and appearance
Macrocytic anemia
Cells larger than normal impaired (folic acid and Vitamin B12 deficiency)
Microcytic anemia
smaller cells (thalassemia)
Hypochromic anemia
Reduced hemoglobin content
Hypochromic microcytic anemia
Smaller than normal and reduced hemoglobin content
Iron-deficiency Anemia
The most common type; Hypochromic microcytic anemia (not enough iron);
When does Iron-deficiency Anemia happen
This happens when there are a lack of iron in the diet, rapids periods of growth in infants, inadequate reutilization of iron, chronic infection/inflammation, cancers, and loss of blood (GI tract, excessive menstrual bleeding, too frequent blood donations)
Laboratory tests in blood for iron deficiency
Serum ferritin (low), Serum iron (low), and Serum iron-binding capacity (high)
Iron-Deficiency Anemia Treatment
Learning the cause of anemia, treatment on cause than symptoms, administering supplementary iron
Vitamin B12 deficiency anemia
Those who are vegetarian are at risk; found in meat, milk, and foods rich in animal proteins; For structural and functional integrity of the nervous system; deficiency may lead to neurologic disturbances
Folic acid
Green leafy vegetables and animal protein foods; are required for normal hematopoiesis and normal maturation of many other types of cells
Absence or deficiency of vitamin B12 or folic acid
Mature red cells are larger than normal or macrocytes; corresponding anemia is called macrocytic anemia, Leukopenia (low WBC), thrombocytopenia (low platelets), Abnormal red cell maturation or megaloblastic erythropoiesis
Folic Acid Deficiency Anemia Pathogenesis
Inadequate diet: Encountered frequently in chronic alcoholics
Poor absorption caused by chronic intestinal disease
Occasionally occurs in pregnancy with increased demand for folic acid
Pernicious Anemia (macrocytic anemia)
Lack of intrinsic factor (B12); causes included gastric mucosal atrophy, Autoantibodies directed against gastric mucosal cells and intrinsic factor, Surgery to remove sections of the stomach, and Chronic intestinal diseases (Crohn’s, IBD)
Pernicious Anemia treatment
Increased oral dose (B12 supplements) or Intramuscular injections
Conditions that depress bone marrow function
Anemia of chronic disease: Mild suppression of bone marrow function (parvoirus B19), Aplastic anemia (Marrow injured by radiation, anticancer drugs or chemicals, Autoantibodies, CTL autoimmunity)
What does bone marrow suppression affect?
WBC and platelets - Pancytopenia (anemia, leukopenia, thrombocytopenia)
Bone marrow treatment
Depends on the cause; Blood and platelet transfusions, Immunosuppressive drugs, Hemopoietic stem cell transplant in highly selected cases of aplastic anemia, or no specific treatment
Hereditary hemolytic anemia
Genetic abnormality prevents normal survival, Abnormal shape (Hereditary spherocytosis; These cells have no central pallor), Abnormal hemoglobin (Hemoglobin S (sickle hemoglobin) or hemoglobin C), Defective hemoglobin synthesis (Thalassemia minor and major; globin chains are normal, but synthesis is defective)
Thalassemia
Defective synthesis of alpha or beta globulin
Alpha – (4 genes)
1- no change 2 -trait with mild disease, 3 severe disease, 4 – incompatible with life (hydrops fetalis)
Unstable Beta tetramers
Defective Oxygen exchange; formed by lack of alpha and excess beta chains
Beta – (2 genes)
Heterozygous-mild, homo-severe
Sickle cell
Hemoglobin S (beta Hgb point mutation); Present in areas where Malaria is/was common; Constant sickling wears out cells and sickled cells are targeted for early destruction by the spleen, cells can also form blockages, chronic joint pain also occurs
Sickle cell trait vs. Sickle cell disease
Trait: heterozygous, generally asymptomatic, Disease: homozygous, chronic health problems
Vaso-occlusive crisis
Severe, abdominal pain (kidney, liver spleen infarction)
Acquired Hemolytic Anemia
Normal red cells that are unable to survive due to a hostile environment; Attacked and destroyed by antibodies and Destruction of red cells by mechanical trauma
Clotting Disorders
Disseminated intravascular Coagulation (DIC), Thrombotic Thrombocytopenic Purpura TTP –clots form in small blood vessels damaging RBC
Diagnostic Evaluation of Anemia
History and physical examination, Complete blood count to assess the degree of anemia, leukopenia, and thrombocytopenia, Blood smear to determine if normocytic, macrocytic, or hypochromic microcytic, Reticulocyte count to assess the rate of production of new red cells, lab tests, bone marrow study, and evaluation of blood loss
Secondary polycythemia
Common, Reduced arterial oxygen saturation leads to a compensatory increase in red blood cells (increased erythropoietin production)
Primary or polycythemia vera
Rare, Manifestation of diffuse marrow hyperplasia of unknown etiology (cause), an overproduction of red cells, white cells, and platelets; can evolve into granulocytic leukemia
Polycythemia Complications
Clot formation due to increased blood viscosity and platelet count
Polycythemia Treatment (both types)
Primary polycythemia: Treated with drugs that suppress marrow function
Secondary polycythemia: Periodic removal of excess blood
Secondary thrombocytopenic purpura
Damage to bone marrow from drugs or chemicals; Bone marrow infiltrated by leukemic cells or metastatic carcinoma
Primary/ Immune thrombocytopenic purpura (ITP)
Associated with platelet antibodies where the bone marrow produces platelets, but they are rapidly destroyed, chronic in adults (immune suppression for treatment)
Lymphatic System function
Provide immunologic defenses against foreign material via cell-mediated and humoral defense mechanisms and provides return of lost circulatory volume to vascular system
Lymph nodes
Bean-shaped structures consisting of a mass of lymphocytes supported by a meshwork of reticular fibers that contain scattered phagocytic cells
Where is lymphoid tissue
Present in thymus, tonsils, adenoids, lymphoid aggregates in intestinal mucosa, respiratory tract, and bone marrow
Thymus
Overlies base of the heart; large during infancy and childhood; undergoes atrophy in adolescence (essential in the prenatal development of the lymphoid system and in the formation of body’s immunologic defence mechanisms ( T cell development/ selection))
Spleen
Specialized to filter blood (Macrophages, antibodies, lymphocytes and sinusoids to detect and remove pathogens in blood)
Reasons for splenectomy
Traumatic injury: To prevent fatal hemorrhage
Blood diseases: Excessive destruction of blood cells in the spleen (hereditary hemolytic anemia)
Prevent chronic splenomegaly
Cancer – Leukemia, Lymphoma
Effects/risks of a splenectomy
Less-efficient elimination of bacteria (especially if blood-borne)
Impaired production of antibodies
Predisposed to systemic infections
Risk of increased platelet/RBC
Which infections are splenectomy patients at risk of?
Streptococcus pneumoniae, Haemophilus influenzae, and meningococcus infections
Treatment for Splenectomy
Vaccines and antibiotic prophylaxis
Infectious mononucleosis
Lymphatic System disease; usually caused by Epstein-Barr virus (EBV-B-cell 90%) or CMV – Tcell/macrophages (5-7%)
Risk: spleen may rupture during high-contact sports and in those with compromised immune systems (give rise to B cell lymphoma)
Enlarged LN cancers
Metastatic tumors: Breasts, lung, colon, other sites, Malignant lymphoma (Hodgkin lymphoma
and Non-Hodgkin lymphoma), and Lymphocytic leukemia
Leukemia
A neoplasm (Cancer) of hematopoietic tissue; Leukemic cells diffusely infiltrate the bone marrow and lymphoid tissues, spill over into the bloodstream, and infiltrate throughout various organs of the body
Aleukemic leukemia
Condition in which white cells are confined to the bone marrow such that their number in the peripheral blood is normal or decreased
Myelodysplasia (Preleukemia)
A disturbed growth and maturation of marrow cells; 3 types: Anemia (Reduced number of erythrocytes), Leukopenia (Reduced number of white cells), Thrombocytopenia (Reduced number of platelets)
Not all patients develop leukemia
Common types of hematopoietic cells that give rise to leukemia
Granulocytic, Lymphocytic, and Monocytic
CLL, CML, ALL, AML
chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and acute myeloid leukemia
Splenomegaly
Enlarged spleen
Hepatomegaly
Enlarged liver
Lymphadenopathy
Enlarged lymph nodes
Bone pain in Leukemia
Expansion of cells in bone marrow
Chronic leukemia
The evolution of disease proceeds at a relatively slow pace and often can be controlled
Acute leukemia
A rapidly progressive disease, more difficult to control
Diagnosis Leukemia
flowcytometry (phenotyping) bone marrow biopsy, Karyotyping (numbers, disease-specific risk genes – BCR/ABL fusion)
Lymphoma
When cancerous cells form solid tumors in LN; mostly diseased B-cells or some T-cells which disrupt immune function
Hodgkin Lymphoma
young adults, start in single LN and spreads to others and eventually other parts of the body. Usually detected early as a single or group of enlarged LN
Reed-Steinberg cells
(large atypical B-cells) that act as nucleus of tumor and secrete cytokines to attract other tumor cells
Non-Hodgkin
Older adults, variable in appearance an progression, often not detected until widespread dissemination has occurred
Treatment of Leukemia and Lymphoma + survival rate
Destruction of malignant cells by chemotherapy or radiation to produce remission (3 phases: Induction/Consolidation/Maintenance)
Other treatments:
- Hematopoietic Stem Cell Therapy (BMT, peripheral, cord blood): replaces malignant cells (must use immune suppression drugs)
50% 5 year survival rate if HLA match is found
HCV
slowly progressive cell injury
