Basic immunology and hypersensitive disorders beba

1. Basic Immunology
and Hypersensitivity
Disorders
Prepared by- Bisrat G. / ORL-HNS (R1)
Moderator - Dr. Alene M. / ORL - HNS Surgeon
April 2018 GC

2. Outline
 Introduction
 Innate Immunity
 Adaptive Immunity
 Cell mediated
 Humoral
 Cells of Immune system
 Immunopathology
 Bibliography

3. Introduction
 Immunity / L. immunis/ - “exempt” protection from
disease.
 Immunity - the ability to resist almost all types of organisms or toxins that tend
to damage the tissues and organs.
 Not only does the immune system protect the organism from infectious microbes;
it also avoids responses that produce damage to host tissues.
 The immune system evolved as the host’s defense against infectious agents.

4. Cont…
 The immune system is divided into the innate and adaptive systems.
 The following features of the adaptive immune system distinguish it from
the innate system:
 Specificity of antigen recognition,
 Diversity of the antigen receptor repertoire,
 Adaptiveness to the changing environment, and
 Immunologic memory.
 The innate immune system recognizes foreign invaders immediately via
pattern recognition receptors, whereas the adaptive immune system
takes time to mount a response.

5. Cont…
 Broadly defined, the innate immune system consists of all aspects of the host
defense mechanisms that are encoded in the germline genes of the host.
 These include barrier mechanisms, such as epithelial cell layers, the secreted
mucus layer that overlays the epithelium, and the epithelial cilia that sweep
away this mucus layer.
 The innate response also includes soluble proteins and small bioactive
molecules that either are constitutively present in biologic fluids.
Activated phagocytes (including neutrophils, monocytes, and macrophages) are also part of the
innate immune system.

6. Cont…
 Mucosal surfaces of the upper airway are less resistant than the skin and
are thus more common portals for offending pathogens.
 The innate immune system reduces that vulnerability through the
presence of various physical and biochemical factors.
 A good example is the enzyme lysozyme.
 If an offending organism penetrates this first line of defense, bone
marrow–derived phagocytic cells attempt to engulf and destroy it.

7. Cont…
 Unlike the innate mechanisms of defense, the adaptive
immune system manifests exquisite specificity for its target
antigens.
 Adaptive responses are based primarily on the antigen-
specific receptors expressed on the surfaces of T and B
lymphocytes.

8. Innate Immune System
 Is the first line of defense against foreign substances.
 It comprises both physical barriers and an array of receptors and antimicrobial
compounds.
 The sinonasal barrier comprises ciliated epithelial cells, subepithelial glands,
goblet cells, and the mucus blanket.
 The cells associated with innate immunity include neutrophils, monocytes,
mast cells, eosinophils, basophils, and dendritic cells (DCs ).
 There are several classes of PRRs: Toll-like receptors (TLRs), RIG-I-Iike
receptors, Nod-like receptors, and C type lectin receptors

9. Cont….
 These highly conserved sequences, known as pathogen-associated molecular
patterns (PAMPs ), include
 Peptidoglycan and lipoteichoic acid from gram-positive bacteria,
 Lipopolysaccharide (LPS) from gram-negative bacteria, and RNA from viruses.
 NB : The responses of the innate immune system against the PAMPs signal the
adaptive immune system to develop memory and subsequent longer-lasting
immune responses.

10. Antimicrobial Peptides
 The Important player in the innate immune response is the numerous antimicrobial
peptides that are expressed in the sinonasal and lower airway epithelium.
 Includes lactoferrin, lysozyme, cathelicidin, defensins, secretory leukocyte proteinase
inhibitor.
 In addition to being referred to as endogenous antibiotics by being secreted in
response to microbes, these peptides also play a role in activating or suppressing
effector cells of the innate and adaptive immune system.

11. NK cells
 originate in the bone marrow and participate in the innate
immune system.
 Upon activation, they are capable of rapid and substantial
production of cytokines, including IL-4, which is an
important cytokine in allergic pathogenesis
 NK cells were first known for their capability to lyse tumors
without any prior priming or immunization.
 There are two different types of NK cells-those that
participate in killing and those that focus on cytokine
production

12.  Another feature of innate immunity is the complement system. The complement
system is the primary humeral mediator of antigen-antibody reactions.
 Initially, complement was thought to play a major role only in innate immunity against
invading pathogens. It was discovered subsequently that the complement system plays
an important role in the adaptive immune system by being involved with both T and B
cells.
 There are three routes by which the complement system is activated:
 the Classical pathways,
 the Lectin pathway; and
 the Alternative pathway.

13. Adaptive Immune System
 Innate immunity controls and eliminates infection with the help of the
complement system, NK cell activation, and TLR activation.
 If the innate immune system is unable to mount an inflammatory response
sufficient to remove pathogens, the adaptive immune response is activated.
 The adaptive immune system utilizes many of the same cells as the innate
immune system. One major difference between the two responses is the mode of
recognition of antigens.

14. Cont…
 The innate immunity recognizes microorganisms through components present on
their cell walls via broad receptor recognition,
 The adaptive immune system recognizes specific antigens that are processed and
presented by antigen-presenting cells in the context of MHC receptors.
 Diverse
 Antigenic specificity
 Immunologic memory
 self recognition

15. Cell mediated Immunity
 In cell-mediated adaptive immunity, priming occurs during the first
exposure to antigen by MHC II on antigen presenting cells (APCs) with the
help of costimulatory molecules.
 TCR receptors on the T cell associate with the CD3 receptor and, in turn,
activate a series of phosphorylation steps within the cell, resulting in the
formation of either CD4+ or CD8+ T cells.
 Activation of T-helper (Th) cells allows the secretion of many cytokines and
mediators which, in turn, activate effector cells such as macrophages.

16. Cell mediated
 T –lymphocytes
 Intracellular microbes
 T-cell receptors
 membrane bound
 recognizes Ag-MHC

17. Humoral Immunity
 Also, in humeral adaptive immunity, the primed Th cell comes into contact with B
cells expressing the same antigen.
 Interaction between these two cell types and linking of CD40 and CD40L on B and
activated Th cells, respectively , causes B-cell activation and differentiation into
antibody secreting plasma cells.

18. Humoral Immunity
 B cell
 Extracellular microbes
 Antibody
1. Recognize antigen
2. Opsonization
3. Activate complement
4. Cytotoxicity

20. CELLS OF THE IMMUNE SYSTEM
 The cells of the immune system are derived from Pluripotent Hematopoietic Cells.
 They develop along two distinct lineages: the Myeloid and the Lymphoid.
 The myeloid stem cell lineage is further divided into granulocytes, megakaryocytes,
platelets, and erythrocytes.
 Pluripotent stem cells also differentiate along the lymphoid stem cell line, of which T cells,
B cells, and NK cells are major players in the immune response to allergy.

22. Neutrophils
 Composed of two interchangeable Subpools: the circulating pool and the
marginal pool.
 Neutrophils are recruited and activated by Th l7 cells in either a direct or
an indirect way. The direct way is through IL-8 production, and the
indirect way is by inducing the production of CSF and CXCL8.
 The neutrophils recognize particles by the opsonins attached to them.

23. Eosinophils
 Produced in the bone marrow from CD34+ hematopoietic precursors.
 They circulate in the blood and localize to inflamed tissues.
 Many cytokines are important in the recruitment of eosinophils to sites of
inflammation, but the most important are IL-l, IL-5, and TNF.
 Cytotoxic and Helminthotoxic
 Survival of eosinophils in tissues is based upon their need for several growth
factors, such as IL-5, IL-3, and GM-CSF

24. Basophils
 Basophils are granulocytes that possess high-affinity IgE receptors. They contain
histamine and other mediators, including cytokines.
 They can contribute to anaphylaxis by releasing histamine.
 They express IL-4, and contribute to allergic reactions at tissue sites such as the
nose, lungs, and skin.

25. Monocytes
 Monocytes originate in the bone marrow from pluripotent stem cells and then are
released into the blood.
 They produce PGs, IFNs, proteases, and cytokines. They play a role in
immunomodulation with their expression of histamine H4 receptor, which is involved
in the perpetuation of allergic inflammation.
 Upon migration from the blood into tissues, monocytes mature into macrophages or
APCs, which are either dendritic or Langerhans cells interspersed in the epithelial
layer of the nasal mucosa and skin.
 It has been found that this maturation is associated with up regulation of H-1
(histamine) receptors.

26. Lymphocytes
T Lymphocytes
 make up 60% to 70% of peripheral lymphocytes.
CD4+T Cells
 interact with cells in the context of MHC-II protein, which is present on APCs.
These cells develop into Th1 and Th2 cells.
CD8+T Cells
 CD8+ cells interact in the context of MHC-I, which is present on all cells. The role
of CD8+ cells in allergy is not clear.
may prevent the development of
airway hyper responsiveness.

28. Cont.…
 B Lymphocytes
 When stimulated by antigen via their IgM surface receptors or B cell receptors
(BCRs ), BCRs associated ligands aggregate to form signaling complexes, whose
strength is modulated and propagated via second messengers such as DAG,
inositol triphosphate, and intracellular calcium release.
 B cells differentiate into plasma cells.
 Plasma cells are responsible for secreting different classes of Igs that mediate
humeral immunity.

29. Dendritic Cells
 Follicular dendritic cells, specialized APCs in the B-cell areas of lymph nodes and
the spleen, are important in the generation and maintenance of memory B cells,
which they achieve by trapping antigen-antibody complexes.
 Peripheral tissue dendritic cells engulf and process antigen, leave the tissues, then
go home to T-cell areas in draining lymph nodes or the spleen.
 In the lymph nodes, these APCs can directly present processed antigens to
resting T cells to induce the latter’s proliferation and differentiation.

30. IMMUNOGLOBULINS
 Igs are glycoproteins
 20% of the total plasma proteins.
 Igs function to tag and aggregate toxins and bacteria. They facilitate the
activation of the complement system as well as the activation of macrophages,
neutrophils, and lymphocytes to clear foreign materials.
 IgG
 IgM
 IgA
 IgE
 IgD

31. CYTOKINES, INTERFERONS, AND
CHEMOKINES
 Cytokines are soluble mediators that have growth, differentiation, and activation
functions for immune responses.
 Cytokines can be grouped into those that are predominantly APCs or T-lymphocyte
derived; that predominantly mediate cytotoxic (antiviral and anticancer), humeral,
cell-mediated, or allergic immunity (Th2); or that are immunosuppressive (Treg
cells).
 Chemokines are a group of small (8 to 12 kD) proteins with the ability to affect cell
migration or chemotaxis.
 Chemoattractants
 These cells include the neutrophils, monocytes, lymphocytes, eosinophils,
fibroblasts, and keratinocytes.

32. Complement System
 important effector of both the innate and
adaptive immune responses.
 mediates immune adherence, phagocytosis,
chemotaxis, and cytolysis.
 The classic pathway comprises C1, C4, and C2.
 The third pathway of complement activation, the
lectin pathway, is triggered by microbial cell wall
components containing mannans.

33. Lymphoid Organs
 The primary lymphoid organs, sites where lymphocytes differentiate and mature
from stem cells into effector cells, include the thymus and bone marrow.
 The secondary lymphoid organs are sites where mature lymphocytes reside and
immune responses are generated.
 Divided into the systemic immune system (spleen and lymph nodes) and the
mucosal immune system (tonsils, Peyer’s patches, intraepithelial lymphocytes, and
the lamina propria of mucosal tissues).

34. Immunopathology
 The two major effector arms of the adaptive immune response are
humoral and cellular.
 In the defense against infections, antibodies are operative against bacteria or bacterial
products; cell-mediated immunity operates primarily against viral, fungal, and mycotic
infections.
 killing effects of immune reactions are extremely effcient and specifcally directed.
 In some situations, this destructive effect of immune reactions is termed Allergy or
Hypersensitivity and is considered an Immunopathologic reaction.
 These reactions are divided into four types

35.  Type I (mast cell– mediated reactions), use the release of mast cell or
basophil mediators to create responses to sensitizing allergens (can be IgE-dependent
(anaphylaxis) or IgE-independent (sensitivity to iodide contrast media) ).
 Type II, /cytotoxic, antibody-mediated reactions/ (IgG-, IgM-
mediated),
1. Binding of IgG and IgM antibodies to antigens on the surface of target cells
2 .Opsonization, complement activation, or cell lysis and ADCC.
These mechanisms can damage self antigens in various tissues.
 One clinical example is known as penicillin-induced autoimmune hemolytic anemia

36.  Type III, /immune complex–mediated reactions/ (IgG, IgM
complex mediated),
 involve antibody-mediated inflammation whereby the antibody and its antigen
form low-solubility immune complexes => activate complement, and set off an
inflammatory response characterized primarily by neutrophil influx, which inflicts
tissue injury.
Immune complex vasculitis in the skin can also occur in a series of clinical conditions, such as systemic lupus erythematosus,
rheumatoid arthritis, drug reactions, and infections.

37.  Type IV, /delayed hypersensitivity (DTH) reactions/ (T cell–
mediated),
 are caused by antibody-independent mechanisms involving T cells or
NK cells.
 These reactions are the pathologic variants of a normal T cell–mediated immune
response in which the T-cell response to an environmental antigen becomes
exaggerated.
 A clinical example of such a reaction, as previously described, is the cutaneous
reaction to challenge with the purifed protein derivative of M. tuberculosis in
previously infected or vaccinated patients.

38. DEVELOPMENT OF ALLERGY
 The development of AR, as that of other allergic conditions, pivots on the interplay
between genetic predisposition and the timing of environmental exposures.
 Subjects with a family history of asthma, eczema, hay fever, and urticaria and a
positive skin test are referred to as atopic.
 A family history of atopic diseases is a risk factor for the development of AR,
asthma, and atopic dermatitis (4-6 X in Asthmatic)
Atopy, the predisposition to respond to environmental allergens with the production of specifc
IgE antibodies.

39. Allergic Rhinitis
 Allergic rhinitis is a clinical hypersensitivity of the nasal mucosa to foreign
substances mediated through IgE antibodies.
 Prevalence of between 10% and 20% (US figure)
 B > G then approximately equal in adults.
 Because individuals require low-dose exposure to an offending allergen over many
years before development of symptoms, seasonal rhinitis rarely
occurs in children younger than 2 years.

40. The Hygiene Hypothesis
 The "hygiene hypothesis• postulates that infections during infancy may protect
against AR and atopy by downregulating the production of IgE.
 Associates reductions of infectious diseases in developed countries with the rise
allergic and atopic diseases.

41. The Allergic Response
 AR develops after sensitization to allergens. Allergens such as pollens, grasses,
dander, and mold are deposited on mucosal surfaces.
 After antigen deposition, DCs sample antigen and migrate to the lymph nodes,
where they present antigen to sensitize T cells.
 Interestingly, it is now thought that allergic individuals possess a mucosal
environment that favors class switching from IgG to lgE.
 lgE-mediated nasal mucosal responses in response to antigen challenge occur in
an early and a late phase.

42. The Early Response
 occurs within minutes after exposure to antigen.
 Patients first sense itching, followed by sneezing. rhinorrhea, watering of the eyes,
then, nasal congestion.
 A large part of this response except for the congestion is due to the release of
histamine and results in vasodilation, vasculature leakage of fluids, glandular; and
neural stimulation.

43. Mast cells
 Mast cells play important roles in the early response and may play a role in the
response to allergen challenge.
 Products of mast cells include but are not limited to, histamine. lipid mediators
such as PGs and leukotrienes, chemokines, as well as cytokines IL-3, IL-4, TNF-a.
 affected by local cytokines that influence their development. maturation, and
death.
 Antigen-specific IgE has the ability to bind with high-affinity receptors on mast
cells on mucosal surfaces.

44.  On exposure to antigen, the antigen-specific lgE on the surface of mast cells cross-
links, causing an influx of calcium ions.1his process results in the exocytosis of
granular content. with the release of preformed mediators such as histamine, heparin,
heparin, and proteolytic enzymes.
Neuronal Contribution
 Sneezing and itching during the early response to allergen provocation
involve the nervous system.
 It has also become clear that the nasal response to allergen is accompanied by an
ocular, pulmonary, and even a sinus response that can, at least in part, be explained by
a neural reflex.

45. The Late Response
 symptoms and inflammatory events that occur hours after antigen exposure.
 The eosinophils respond to IL-5 produced by T cells, and T cells are likewise
activated to facilitate a cascade of events that precipitate the local
inflammatory reactions seen in the late response.
 IL-4 released by mast cells and T helper cells, also contributes to this cascade of
events.
 Vascular cell Adhesion molecule (VCAM)

48. Evaluation and Diagnosis
 The classic symptoms of seasonal allergic rhinitis are recurrent episodes
of sneezing, pruritus, rhinorrhea, nasal congestion, and lacrimation that
occur after exposure to the offending allergen.
 Itching is the symptom most suggestive of an allergic etiology and involves not only the
nose but also the palate, throat, eyes, and ears.
 Ocular symptoms, including itching, tearing, and conjunctival injection, occur frequently.
Eustachian tube dysfunction, manifested as ear popping and clicking, is an occasional
manifestation.

49. The traditional classifcation of allergic rhinitis is seasonal, perennial, or episodic.
 Seasonal allergic rhinitis is defined by symptoms that occur during exposure to
seasonal allergens, such as ragweed, grasses, outdoor molds, and tree pollens.
 Perennial allergic rhinitis, defined as nasal symptoms for more than 2 hours per
day for more than 9 months of the year, occurs when allergies develop to house
dust mites, indoor molds, animal danders, and cockroaches.
 Episodic rhinitis refers to symptoms on exposure to allergens that are not
normally present in the environment, such as a cat-allergic individual becoming
symptomatic upon entering the home of relatives who have a cat.

50. 1999, during the ARIA (Allergic Rhinitis and its Impact on Asthma) World Health
Organization (WHO)
 Thus according to the ARIA classifcation,
 Intermittent allergic rhinitis refers to symptoms present for less than 4 days a
week, or for less than 4 consecutive weeks, and
 Persistent allergic rhinitis refers to symptoms present for more than 4 days a
week and for more than 4 consecutive weeks, with the realization that patients
usually suffer almost every day.

51.  Diagnostic Tests
 The two most common tests used to confrm the diagnosis of allergic
rhinitis are skin testing and in vitro testing for serum levels of specifc
IgE antibodies.
 Epicutaneously (puncture skin tests) or intradermally (intradermal tests).
 IgE measurement (This test, however, is currently not being
used because it requires a radioactive isotope and expensive equipment.
 MAST (multiple allergen simultaneous test) and the capsulated hydrophobic
polymer system that can provide more accurate in vitro tests and test multiple
allergens, these tests are less sensitive and more
expensive than the in vivo skin testing for allergy detection

53.  Skin Prick testing has certain disadvantages, as follows:
(1) skin reactivity might be affected by previous ingestion of antihistamines
or other drugs,
(2) children often do not tolerate multiple skin needle pricks,
(3) prior or coexisting dermatologic conditions, such as eczema or
dermatographism, may preclude the performance of skin tests,
(4) the potency of antigen extracts needs to be maintained, and
(5) systemic reactions may occur.

54. Therapeutic Options
 Avoidance
 Pharmacotherapy
 step-wise, depending on the severity and duration of the symptoms
 The medications used are:
 oral antihistamines,
 intranasal antihistamines,
 intranasal steroids,
 leukotriene receptor antagonists,
 intranasal cromolyn,
 decongestants, and
 saline irrigations.

55.  Immunotherapy
 Allergen-specific immunotherapy (SIT) provides relief for patients who have
symptoms.
 It modulates the immune system, and has the potential to alter the natural
history of the disease.

57. Bibliography
 Paul W. cummings 5th ed. Part 4, Chap 40; Immunology of the Upper Airway and
Pathophysiology and Treatment of Allergic Rhinitis p. 597- 623.
 Byron J. Bailey ORL HNS Vol 1 5th ed. Section 2, Chap 25; Immunology and Allergy
p. 379- 406.
 Websites

58. THANK
YOU