immunology (infectious agents)

Innate immunity

Immediate, non-specific first-line defense made up of physical barriers (skin, mucous membranes) and cellular components (neutrophils, macrophages)

Adaptive immunity

Specific, slower response made up of B cells (antibody-mediated), T cells (cell-mediated), and memory cells that give long-term protection

Components of innate immune defenses

Epithelial barrier, secretions, endogenous microflora, resident phagocytes, pattern recognition receptors

Epithelial barrier (innate)

Skin, respiratory epithelium, and enterocytes

Innate secretions

Mucus, sweat, sebum, cerumen, acid, enzymes, defensins, polyreactive antibodies, surfactant

Pattern recognition receptors (PRRs)

Innate receptors that recognize pathogen-associated molecular patterns (PAMPs) on pathogens

Pathogen-associated molecular patterns (PAMPs)

Conserved molecular structures on pathogens that are recognized by PRRs

TLR1 recognizes

Triacyl lipopeptide (bacteria)

TLR2 recognizes

Peptidoglycan, lipoteichoic acid, zymosan, lipoprotein (Gram-positive bacteria, fungi, Mycoplasma)

TLR3 recognizes

dsRNA (viruses)

TLR4 recognizes

Lipopolysaccharide (LPS) of Gram-negative bacteria

TLR5 recognizes

Flagellin (bacteria)

TLR6 recognizes

Peptidoglycan and lipoteichoic acid (Gram-positive bacteria)

TLR7 and TLR8 recognize

ssRNA (viruses)

TLR9 recognizes

Non-methylated DNA (viruses and bacteria)

RIG-I and MDA5 recognize

dsRNA (viruses); cytoplasmic PRRs

Dectin-1 and Dectin-2 recognize

b-Glucans and a-mannans (fungi)

NOD-like receptors (NLRs) recognize

Peptidoglycan and toxins (bacteria)

Four steps of adaptive immune defense

Antigen recognition, clonal selection, effector responses, memory cell formation

Antigen recognition (adaptive)

Lymphocytes recognize specific antigens on pathogens

Clonal selection

Selected lymphocytes that recognize the antigen multiply

Adaptive effector responses

B cells produce antibodies; T cells eliminate infected cells

Memory cells

Lymphocytes that persist after infection and allow a faster response upon reinfection

TH1 cells act on

Macrophages via IFN-γ to kill intracellular bacteria and protozoa; also help B cells

TH2 cells act on

Mast cells, basophils, and eosinophils via IL-4, IL-5, IL-13 to fight helminths; also help B cells

TH17 cells act on

Neutrophils via IL-17 to fight fungi and extracellular bacteria; also help B cells

Cytokine released by TH1 cells

IFN-γ

Cytokines released by TH2 cells

IL-4, IL-5, IL-13

Cytokine released by TH17 cells

IL-17

Steps of TC cell activation

1) Antigen presentation to T-helper cell on MHC II 2) Helper T cell releases cytokines 3) Activation of cytotoxic T cell 4) Binds infected cell via MHC I 5) Cell death

Molecules released by TC cells to kill infected cells

Perforin, granzymes, and granulysin

MHC class II function

Presents pathogen antigen from phagocytes to T-helper cells

MHC class I function

Presents peptide on infected cells to cytotoxic T cells

Four functions of antibodies

Block pathogen entry (neutralization), stimulate phagocytosis (opsonization), activate complement, mediate ADCC

Primary immune response

Initial response to first exposure to an antigen; slower, weaker, lower antibody levels, forms memory cells

Primary response latency

Delay while the immune system recognizes the new antigen and produces the necessary immune cells and antibodies

Primary response protection

Provides some protection but may be insufficient to fully eliminate the infection

Secondary immune response

Response to re-exposure to the same antigen; rapid, strong, higher antibody production, long-lasting, highly specific

Why the secondary response is faster

Memory B and T cells quickly recognize the antigen and trigger a robust response

Primary vs secondary antibody levels

Secondary response produces higher antibody levels than the primary response

Does the presence of bacteria indicate disease?

No, the presence of bacteria does not indicate disease

Key innate cells against bacteria

Neutrophils and macrophages, which recognize and engulf bacteria

Complement role against bacteria

Assists bacterial destruction through opsonization and lysis

Humoral immunity against bacteria

Bacterial antigens stimulate B cells to produce antibodies

T cell role against bacteria

Activate macrophages and cytotoxic T cells, which can directly kill infected cells (cell-mediated immunity)

Memory cells in bacterial infection

Memory B and T cells provide long-term protection against recurring bacterial infections

TLRs involved in innate recognition of bacteria

TLR1, 2, 4, 5, 6, and 9

Innate response to bacteria

Cytokine release, complement activation, inflammation, phagocytosis, and sequestration of nutrients

Nutrient sequestration (innate response to bacteria)

Withholding of iron and tryptophan from bacteria

Adaptive immunity against extracellular bacteria

Humoral immunity (antibodies)

Antibody mechanisms against extracellular bacteria

Toxin neutralization, opsonization, killing by the classical complement pathway, phagocytosis by activated macrophages

Antibody isotypes for neutralization of bacteria

IgG and IgA

Better opsonizing antibody against bacteria

IgM is better than IgG

ADCC against extracellular bacteria

Less important

Adaptive immunity against intracellular bacteria

Cell-mediated immunity

Cell-mediated mechanisms against intracellular bacteria

Th1 cells activate macrophages for killing; destruction by cytotoxic T cells and NK cells

Canine pyoderma

Common bacterial skin infection in dogs, often caused by Staphylococcus spp.

Innate response in canine pyoderma

Neutrophils and macrophages in the skin recognize bacterial invasion, engulf and destroy bacteria

Adaptive response in canine pyoderma

If the infection persists, B cells make antibodies, T cells assist, and memory B and T cells form

Bacterial evasion of innate defenses

Interfere with TLR signaling, modify PAMPs, interfere with intracellular signaling, resist antibacterial peptides, block phagocytosis

Intracellular bacteria evasion of innate defenses

Interfere with phagosomal maturation or escape the phagosome

Bacterial evasion of adaptive immunity

Antigenic variation and secretion of proteases that destroy antibodies and cytokines

Bacterial survival within macrophages

Avoids exposure to adaptive immunity (e.g., Mycobacterium spp.)

Innate immunity against viruses

Antiviral proteins called interferons (IFNs)

Viral PRRs (cytoplasmic)

RIG-I and MDA5

Viral PRRs (endosomal)

TLR3, 7, 8, 9

Triggers of innate response to viruses

Recognition of viral patterns by PRRs and cell damage caused by the infection

Interferons (IFNs)

Glycoproteins that regulate gene expression; a central player in innate defense against viruses

Three types of interferons

Type I, Type II, Type III

Type I interferons

IFNα (produced by dendritic cells) and IFNβ (produced by all cells)

Type II interferon

IFNγ, produced by T cells

Type III interferons

Various; produced by mucosal epithelial cells

Timing of type I interferon production

Within hours, before antibodies appear

Type I interferon signaling pathway

Activates JAK/STAT pathways leading to production of antiviral proteins

Actions of type I interferons

Directly inhibit viral uptake and replication, induce apoptosis, and sensitize cytotoxic T cells

How antibodies prevent viral infection

Block viral invasion, stimulate phagocytosis, trigger complement-mediated virolysis, promote viral clumping

Do antibodies directly destroy viruses?

No, antibodies do not act by direct virus destruction

Antibody-dependent cellular cytotoxicity (ADCC)

Targets infected cells for destruction by NK cells and cytotoxic T cells

Sites where antibodies block viral spread

Transport across epithelium, cell-to-cell transmission, and viral entry to target cells

Long-term antiviral humoral immunity

Provided by long-lived plasma cells and memory B cells

Cytotoxic T cells in viral infection

Recognize infected cells prior to rupture via peptide-MHC-I complexes and induce apoptosis

Helper T cells in viral infection

Activate and support macrophages (phagocytosis), cytotoxic T cells (killing), and B cells (antibody production)

Memory T cells in viral infection

Contribute to long-lasting immunity against viral infections

Feline immunodeficiency virus (FIV)

Viral infection in cats that affects the immune system, similar to HIV in humans

Antibody response in FIV

B cells produce antibodies, but FIV often persists leading to chronic infection

Cell-mediated response in FIV

Cytotoxic T cells play a critical role in controlling FIV by targeting infected cells

Viral evasion strategy of RNA viruses

Antigenic variation

Viral evasion strategy of DNA viruses

Antigenic variation plus immunoregulatory (immunosuppressive) genes

Viral evasion of interferon

Proteins that block IFN signaling

Viral evasion of cell-mediated immunity

Proteins that interfere with MHC-I antigen presentation; evasion of NK cells

Viral evasion of humoral immunity

Non-neutralizing or slowly neutralizing antibodies and antigenic variation

Parasite

Organism that lives in/on a host and gets nutrients from the host or at the expense of the host

Three categories of eukaryotic parasites

Protozoa, helminths, arthropods

Protozoa

Single-celled parasites; can be intracellular or extracellular

Helminths

Multicellular, extracellular parasites

Arthropods (as parasites)

Multicellular, extracellular parasites (fleas, ticks, mosquitoes, mites, lice)

Innate cells involved in parasitic infections

Eosinophils and mast cells; innate responses also trigger inflammation at the infection site

Adaptive response to parasites

B cells make antibodies against parasitic antigens; Th2 cells activate other immune cells and promote antibody production

Eosinophil activation in parasitic infection

Recognize antigens through IgE, triggering activation

Eosinophil effector functions against protozoa

Release granules containing enzymes that damage protozoa and produce pro-inflammatory cytokines and chemokines