INNATE IMMUNE RESPONSE

• Humans are constantly exposed to millions of microbial invaders either through

ingestion, inhalation, contact or thru vectors but humans normally do not get infected
unless immunocompromised.
• Immunocompetent persons are protected from these microbes, whether it be bacteria,
viruses, fungi or worms.
• Man’s ability to to avoid these microbial invaders is due to the innate and the adaptive
immune responses but the adaptive IR are slow to develop (lag period) after exposure
to a pathogen for the first time because specific clones of B and T cells have to expand
after activation. So, man has to rely on the innate IR, if not, the pathogen will continue to
multiply and cause infection / disease in a few days.
• Innate IR are non-specific unlike the adaptive IR
• It depends on a group of proteins and phagocytes that recognize pathogens and are
rapidly activated to help destroy foreign invaders
• Are required to activate the adaptive IR

Components of the Innate Immune Response

• Epithelial surfaces
• Phagocytosis
• Complement fixation/activation
• Inflammatory responses

Components of the Innate Immune Response

• Epithelial surfaces:
• Skin
• Lungs
• Gut
• Vagina
• Mucus layer – mucin and glycoproteins
• Defensins – most abundant antimicrobial peptides that kill bacteria (G+ and
G), viruses and fungi, parasites
• Cilia

• Microorganisms may occassionally breach the epithelial barrier, it is now the job of
the innate and adaptive IR to recognize and destroy these microbes
 • When a pathogen is able to invade the tissues, an inflammatory response is almost
always elicited which may be initiated by resident immune cells already present in
the involved tissue:
• Macrophages, dendritic cells, histiocytes, Kupfer cells and mast cells
• Possess surface receptors known as PRRs (Pathogen-recognition
receptor), which recognize and bind to two subclasses of molecules:
PAMPs (pathogen associated-molecular patterns) and DAMPs (damage-
associated molecular patterns)

Inflammatory Response
• Characterized by (“PRISH”):
• Dolor (pain)
• Calor (heat)
• Rubor (redness)
• Tumor (swelling)
• Functio laesa
• Two phases:
• Vascular phase
• Involves the movement of plasma fluid, containing important
fibrin and immunoglobulins (antibodies), into inflamed tissue
• Cellular phase
• Extravasation of neutrophils, lymphocytes and monocytes
Innate Immune Response
• The innate IR relies on the recognition of molecules (Pathogen-associated
immunostimulants) that are common to many pathogens but are absent in the host
• Pathogen-associated immunostimulants stimulate inflammatory
responses and Phagocytosis
• Pathogen-associated immunostimulants
• Formylmethionine-containing peptides act as very potent chemoattractants for
neutrophils
• Peptidoglycan, Lipopolysaccharide (LPS) and Teichoic acids on bacteria
• Zymosan, glucan, and chitin of fungi
• Glycosylphosphatidylinositol in Plasmodium
• Short sequences in bacterial DNA
• Pathogen-associated immunostimulants are recognized by receptors
called pattern recognition receptors
• The receptors initiate the phagocytosis of the pathogen, and they
stimulate a program of gene expression in the host cell for stimulating
innate immune responses (Toll-like receptors - TLR)
 The complement system is known to amplify and complement the activity of
the antibodies but some components of the complerment are alos pattern
recognition receptors and can be activated directly by pathogen-associated
immunostimulants. Complement can be activated thru three pathways, the
classical, MBL and the alternative pathways. When the classical or lectin
pathway is activated, the alternative pathway may also be activated through a
positive feedback loop, amplifying their effects. Smaller complement products
promote an inflammatory response by recruiting phagocytes and lymphocytes
to the site of infection.
 Many of the mammalian cell-surface pattern recognition receptors
responsible for triggering host cell gene expression in response to pathogens
are members of the Toll-like receptor (TLR) family
o TLRs play important parts in innate immune recognition of pathogen-
associated immunostimulants
 Its activation stimulates the expression of molecules that both
initiate an inflammatory response and help induce adaptive
immune responses
 Abundantly found on the surface of macrophages and
neutrophils, as well as on the epithelial cells lining the lung and
gut
 Act as a warning system to alert both the innate and adaptive
immune systems that an infection is developing
 Some proinflammatory molecules stimulate endothelial cells to express
proteins that trigger blood clotting in local small vessels which occlude the
vessels and cut off blood flow >>> prevents the pathogen from entering the
bloodstream and spreading the infection to other parts of the body
 • Viruses do not possess pathogen-associated immunostimulants.
• Infected cells initiate mechanism to eliminate the pathogen
• Two step process
• The cells degrade the dsRNA into small fragments (about 21–
25 nucleotide pairs in length) that bind to any ssRNA in the host
cell with the same sequence as either strand of the dsRNA
fragment, leading to the destruction of the ssRNA
• The dsRNA induces the host cell to produce interferon α (IFN-
α) and interferon β (IFN-β) with autocrine and paracrine
function
• The binding of the interferons to their cell-surface
receptors activates a latent ribonuclease, which
nonspecifically degrades ssRNA
• It also leads to the activation of a protein kinase that
phosphorylates and inactivates eIF-2 shutting down most
protein synthesis in the host cell
• Inhibits viral replication
• WBC persuade virally infected cells to destroy itself.
• IFNs also stimulate both innate and adaptive cellular immune
responses
• IFNs enhance expression of class I MHC, which present viral
antigens to cytotoxic T cells
• IFNs enhance the activity of NK cells inducing the infected cell
to kill itself by undergoing apoptosis
• NK cells selectively destroy cells that express low levels
of MHC I

Adverse consequence of inflammatory response

• Inflammatory responses are so effective in controlling local infections but can have
serious consequences, sepsis
• Systemic release of proinflammatory molecules into the blood causes dilation of
blood vessels, loss of plasma volume, and widespread blood clotting (DIC), which is
an often fatal condition known as septic shock

Mechanisms how pathogens evade the inflammatory response

• Many viruses encode potent cytokine antagonists that block some aspects of
the inflammatory response.
• Some organisms bind cytokines and block their activity
• Salmonella induce an inflammatory response at the initial site of infection (in
the gut), which allow recruitment of macrophages and neutrophils that they then
invade >>> the Salmonella hitch a ride to other tissues in the body
• Viruses have developed strategies to avoid the killing mechanism cytotoxic T cells
as follows
• By inhibiting the expression of MHC I
• Block MHC gene transcription – adenovirus, HIV
• Block peptide translocator – herpes and cytomegalovirus
• Retrotransloction of MHC I into the cytosol – cytomegalovirus
• NK cells take over
• Increase local production of IFN-α and IFN-β activates the killing activity of
NK cells and also increases the expression of class I MHC proteins in
uninfected cells.
• The cells infected with a virus that blocks class I MHC expression are thereby
exposed and become the victims of the activated NK cells

• Phagocytosis (Read your previous notes)

• Oxygen-dependent mechanism
• Oxygen-independent mechanism
• Three pathways of Complement activation(read your previous notes)

END

GOD BLESS YOU!!!