Regional Immunity

• Although the same basic principles underlie immune functions all over the body, the immune
system still displays various characteristics in different body regions according to their specific
buildup and function. Such body regions include:
1. Those whose physiological roles (their functions) require direct interaction with the outside
environment, so they are covered by epithelial barrier tissues and are in direct interaction with
their respective normal flora systems. These areas display immune response peculiarities different
from elsewhere in the body, thus giving rise to such immune system arms as the:
→ Mucosal Immune System: specialized Immune System in body systems lined with mucosa,
mainly immunity in the Gastrointestinal tract, and other mucosal tissues like Genitourinary tract
and Respiratory tract.
→Cutaneous Immune System: Immune System interacting with the skin, thus protects it.
2. Those areas which are particularly susceptible to inadvertent injury by inflammatory and immune
responses, and therefore experience immune privilege.
These regions are: Brain, eyes, testis and fetus of the pregnant woman.

Immunity in areas exposed to the environment:

• The basic organization of those immune systems is:
1. Integration of innate and adaptive immune mechanisms (incorporate & work together to achieve
the strongest possible Immune Response).
2. Outer epithelial layers to prevent microbial invasion (prevent microbial entry to the body).
3. Underlying connective tissues (e.g. lamina propria in mucosal areas, dermis in skin) which contain
scattered immune cells of various types (e.g. lymphocytes, dendritic cells, macrophages), some of
which may be peculiar to that specific region.

→In mucosal areas, these immune cells might take also the form of local specified arrangements
called mucosa-associated lymphoid tissues (i.e. MALTs).

4. Draining local lymph nodes (lymph drained from those areas goes to local Lymph Node where the
Immune Response might take place.
5. Preferential homing of lymphocytes to the specific region in which they were initially activated.
6. Importance of regulation to prevent unnecessary responses to nonharmful substances.

Mucosal Immune System:

The main features of the mucosal immune system are:
1. Relatively impermeable epithelial barriers.
2. Secretion of mucin and defensins.
3. Localized subepithelial collections of lymphoid tissue (i.e. MALTs).
4. Constant sampling of antigens beyond the barrier by immune cells from within.
5. Integration of proinflammatory and regulatory signals generated by microbial products binding to
immune receptors on epithelial and dendritic cells (to differentiate between harmful & harmless
objects).
6. Reliance on secretory IgA-mediated humoral responses.
7. Stimulation of particular types of effector and regulatory T cell responses.
Immunity in the Gastrointestinal Tract:
• The gastrointestinal tract (GIT) is characterized by its large surface area and abundance of normal
flora, which creates challenges in identifying potentially harmful microbes and telling them apart
from the much more numerous normal flora microbes.
• Both the innate and adaptive immune
responses play an important part towards
achieving that goal.
• Various GI epithelial cell types play different
roles related to immunity:
1) Goblet cells: located at the top of the intestinal
villi and secrete mucus.

2) Paneth cells: located at the bottom of the crypts

and secrete antibacterial peptides.
3) Microfold (M) cells: found in the dome
structures overlying lymphoid tissues and act in
antigen sampling.

→ 1&2 play roles in innate immunity, while 3 plays a role in adaptive immunity.
→ Ag sampling is taking the Ag from the lumen to the underling tissue, specifically to the immune
cells, to determine whether it’s harmful or not.

Innate immunity in the GIT:

1) Mucins: they are secreted and cell surface glycoproteins produced by mucosal goblet cells and
submucosal glands, the composition and rate of production of mucin is affected by various stimuli
(e.g. cytokines, TNF, neutrophil products).

These mucins would then form:

→ Secreted mucus: a single layer in the small intestine, and two layers in the colon, with the
bacteria trapped away from the epithelial surface
→ Glycocalyx(membrane bound/cell surface mucin): which is formed by the combination of
membrane-bound mucins with various glycolipids,
Mucins would provide a barrier against microbes , decoy function, and matrix for display of
antimicrobial peptides.
2) Antibacterial peptides: produced by the intestinal epithelium cells, affect the integrity of microbial
structure.
→Defensins: disrupt the integrity of microbial outer membranes (in Gram negative bacteria)
- -defensins: (e.g. HD5, HD6): produced by the small intestinal Paneth cells as well as by
neutrophils.
- -defensins: produced by colonic crypt cells.
→C-type lectins (e.g. REGIII): bactericidal substances which bind to peptidoglycan (in Gram +ve
bacteria).
by Paneth cells
3) Pattern recognition receptors
→ Membrane-bound: Toll-like receptors (TLRs)
→ Cytoplasmic: nucleotide oilgomerization domain (NOD)-like receptors (NLRs)
- They recognize pathogen-associated molecular patterns (PAMPs) (e.g. lipopolysaccharide,
peptidoglycans), thus promoting responses
against pathogens whilst suppressing those
against commensals.
TLR and NLR activation might lead to:
1. Tightening of interepithelial junctions (Increase
integrity, decrease permeability)
2. Promoting intestinal motility and epithelial
proliferation (Increase integrity)
3. Stimulating the secretion of antimicrobial peptides
and IgA.
- Compartmentalization may help in guiding the
nature of the immune response upon TLR
activation.

4) Innate lymphoid cells (ILCs): derived from the lymphoid lineage but lack specific antigen
receptors. They are activated by cytokines (some of which are called alarmins), after which they
exhibit helper functions analogous to TH subsets.
ILC types include:
→ ILC2s: activated by IL-25 + IL-33 to secrete IL-5 (which activates eosinophils) and IL-13 (which
increases mucus production). Both those functions help in fighting off parasitic infestations. Exhibit
TH2
→ ILC3s: activated by the alarmin IL-1β + IL-23 to produce IL-17 + IL-22, thus promoting
inflammation, defensin production, and tight junction function. Exhibit TH17

Adaptive Immunity in the GIT:

• The major features of adaptive immunity in the GIT are: humoral immunity
1. Relative importance of humoral immunity in the form of secretory IgA. more than CMIR
2. Cell-mediated immune responses are primarily mediated by TH17 cells.
3. Importance of Treg cells in controlling immune responses towards tolerance of antigens from food
and commensal microbes.
‫ال‬
 Distinct from lymph
nodes, GALT
structures are not
encapsulated, and
→Gut-associated lymphoid tissue (GALT) takes the form of such structures as: antigen is delivered
directly to these
• Peyer’s patches(at the beginning of the digestive tract in the intestine) structures, independent
of lymphatics.
• Tonsils (whether lingual, palatine or nasopharyngeal)
• As well as smaller aggregates of lymphoid follicles
- Those follicles are primarily made of B cells, TH cells, follicular dendritic cells and
macrophages.
- The dome areas lie between the follicles and the overlying epithelium, richer in B cells, while
parafollicular areas are particularly richer in T cells compared to other GALT areas.
→ M- Cells: M cells move particulate matter from the lumen first by endocytosis, then by moving the
endosomes across the cytoplasm to the basolateral membrane.
- There, they would be delivered through
exocytosis to B cells and dendritic cells
whether within GALT or scattered in the
lamina propria.
- Unlike macrophages or dendritic cells, M
cells do not process the matter which it
transports and can’t present them to T
cells.
- The antigens delivered to the lamina
propria would then initiate immune
responses whether locally or in draining
lymph nodes.
- During TH cell activation, dendritic cells secrete retinoic acid to imprint a gut-homing phenotype on
B cells and effector T cells through integrin- and chemokine receptor-dependent mechanisms.

Humoral immunity in the GIT:

→ Secretory IgA (whether produced locally or, in the case of breastfeeding, secreted in colostrum or
breast milk) is the main antibody isotype in the GIT, and it mainly acts through neutralization( direct
binding with the Ag and stop it’s pathogenicity) or reducing microbial motility( i.e by binding to
bacterial flagella).
→ Chemicals which mediate IgA isotype switching include the cytokines TGF-β and APRIL, retinoic
acid, and nitric oxide.
→ IgA-producing plasma cells in the lamina propria secrete IgA in the form of a dimer of 4-chain basic
units where a J chain is bound to the Fc
regions of the chains.
The dimer would then bind to the poly-Ig
receptor, move across the cytosol
through transcytosis, then released from
the apical membrane through cleavage
of the poly-Ig receptor (on the basal
area of the epithelium, can transport
both IgA and IgM that’s why it’s called
poly), thus giving rise to the secretory
component).
Other Aspects of Adaptive Immunity ( T cells):
• Most of the intraepithelial T cells are CD8+ with a significant T
cell population, while elsewhere in the gut the CD4+ T cells
predominate. such lamina propria

• As antigen-presenting cells, dendritic cells and macrophages

sample antigens which have breached the epithelial barrier,
and sometimes even send projections across the epithelium to
take samples from the lumen. ( sampling )

• The TH17 pattern predominates in the gut, with less occurrence

of the TH2 and TH1.
• Treg cells are also relatively abundant in the gut, as their
formation is usually induced by TGF and retinoic acid, and
they usually exert their action through producing IL-10.

Immunity in Other Mucosal Areas:

Immunity in the respiratory tract→ it shares many features with that of the GIT.
• It produces mucus and defensins + cathelicidins (which have antimicrobial properties)
• It also produces surfactant proteins (which are involved in viral neutralization, microbial
clearance and inflammatory suppression)
Note: The mucociliary escalator is an active mechanism to keep the tract free from any foreign debris

Immunity in the genitourinary tract→ shows less prominence of MALTs compared to other
mucosal areas(mostly scattered), and it is peculiar in the fact that most of the antibodies in genital
secretions are of the IgG isotype (Remember: In the GIT IgA predominates)

Cutaneous Immune System

• The other Immune System that is exposed to the
environment is Cutaneous Immune System.
(Innate)→ Besides providing a physical barrier function,
the epidermal keratinocytes produce antimicrobial
peptides (e.g. defensins, cathelicidins) and various
cytokines.
→ If this barrier is breached, dermal macrophages, mast
cells and ILCs (Innate lymphoid cells) initiate innate
immune responses. i.e: ILCs 1, which exhibit TH1 cells,
and they are activated by IL-18 and produce IFN
→ PAMPs and damage-associated molecular patterns
(DAMPs) activate pattern recognition receptors (e.g.
TLRs)
(Adaptive)→ Antigen processing and presentation in the skin is carried out by the epidermal
Langerhans cells and the dermal langerin-expressing dendritic cells .These APC interact with the
cutaneous T cell population, 95% of which have a memory phenotype (98% of which reside in the
dermis and only 2% in the epidermis)
→ Upon T cell activation, vitamin D appears to play a major role in imprinting homing pattern on
them. (Remember: In GIT mucosa retinoic acid plays this role).

Immune-Privileged Areas
Areas that are overly sensitive to the adverse effects of immune reactions, therefore the immune
response is tweaked away towards a more suppressed one. These areas include:
1) Brain. 2) Eyes. 3) Testis. 4) Fetus of the pregnant mother

• Mechanisms which suppress immune and inflammatory responses in the Brain:

1. The tight junctions among the local microvascular endothelium (i.e. blood-brain barrier)
2. The action of neuropeptides
3. Scarcity of dendritic cells (relatively low amount of them)
4. The relatively high threshold for microglial activation
→ Even though, a basic level of immune response still takes place there.
The evidence: The occurrence of opportunistic infections in the brain and the presence of local
lymphatics.
• Features which contribute to immune privilege of the Eye:
1. Corneal avascularity
2. The blood-eye barrier near the anterior chamber (bacause of the tight junctions)
3. Absence of lymphatics there
4. Presence of soluble factors with immunosuppressive and antiinflammatory properties in the
aqueous humor.

• Features which contribute to immune privilege of the testis:

1. A blood-tissue barrier which limits cellular access into testicular tissue
2. The antiinflammatory effects of androgens (i.e Testosterone)
3. immunosuppressive effects of TGFβ

• Fetus of the Pregnant Mother: the fetus represents a naturally-occurring allograft, so various
mechanisms are needed to prevent the maternal Immune System from attacking it and
terminating the pregnancy. These mechanisms are:
1. Trophoblastic expression of HLA-G : a nonpolymorphic class I MHC molecule which inhibits NK
cell function and don’t express cytotoxic T cells
2. Lack of costimular molecules in the trophoblast cells
3. functional inhibition of immune responses in the decidua(part of placenta)
4. Treg cells’ role in maternal tolerance of the fetus.
Helful videos:
https://www.youtube.com/watch?v=H-0S7R0cn6U

questions:
1- the J chain is produced by:
a) Helper T cells
b) Dendritic cells
c) Mucosal epithelial cells
d) Macrophages
e) Plasma cells
2- Which of the following substances is a C-type lectin:
a) Mucin
b) Retinoic acid
c) HD5
d) REGIII (alpha)
e) TNF

3- All of the following are immune privileged sites, except:

a) Testes
b) Eyes
c) Brain
d) Breast
e) Fetus

4- All of the following are chemicals that mediate IgA isotype switching except:
a) TGF-β
b) APRIL
c) retinoic acid
d) nitrous oxide.
e) All of them are correct.
5- An example on alarmin is:
a) IL-23
b) IL-17
c) IL-22
d) IL-13
e) IL-1 (Beta)
6- All of the following are related to immunity in the GIT, except:
a) Mucins
b) Defensins
c) M cells
d) TLR and NLR
e) IgM
Answers: 1-e 2-d 3-d 4-d 5-e 6-e