Imunopatologia 2022 - 2023

Imunopatologia
3º Ano Mestrado Integrado em Medicina

Elsa Cardoso
cardoso.elsamaria@fcsaude.ubi.pt
UBI, 08/09/2022
Tópicos do seminário
• Conteúdos
1ª Parte: Alergia, hipersensibilidades e inflamação crónica
2ª Parte: Tolerância e autoimunidade
• Objetivos e competências
• Bibliografia
Objetivos e competências
1ª Parte 2ª Parte
1. Distinguir os quatro tipos principais de 1. Rever os princípios da Imunologia do 2º ano,
hipersensibilidade e compreender os mecanismos especificamente aqueles relacionados com a
imunológicos subjacentes. estrutura e diversidade das moléculas MHC,
2. Para cada um dos quatro tipos de desenvolvimento linfocitário e regulação
hipersensibilidades, reconhecer as funções imunológica, integrando com os conceitos de
benéficas das respostas imunes na eliminação de indução e manutenção de tolerância imunológica e o
agentes patogénicos, assim como os efeitos desenvolvimento de doenças autoimunes.
nefastos destas respostas quando se trata de 2. Distinguir os eventos de fatores envolvidos na
reações de hipersensibilidade. tolerância central versus periférica e prever o
3. Discutir os papeis dos fatores ambientais e impacto de algumas mutações em cada uma destas
genéticos na predisposição para alergias, vias de tolerância.
particularmente no contexto do modelo discutido 3. Conhecer detalhes de algumas síndromes
para a indução de respostas alérgicas. autoimunes; ser capaz de categorizar/agrupar
4. Descrever como respostas inflamatórias locais doenças autoimunes pelo tipo de células/moléculas
benéficas se podem tornar respostas inflamatórias efetoras, ou de acordo com o(s) órgão(s) alvo
crónicas prejudiciais, e dar exemplos por infeções (específicas de órgão versus sistémicas).
ou causas não infeciosas. 4. Compreender o desenho de imunoterapias para
tratamento de doenças autoimunes aplicando os
conhecimentos básicos dos princípios moleculares e
celulares subjacentes.
Bibliografia
• Kuby Immunology. Jenni
Punt, Sharon Stranford,
Patricia Jones & Judith A.
Owen. 8th Edition. 2019. W.
H. Freeman and Company.
Macmillan education
• Janeway´s Immunobiology.
Kenneth Murphy, Casey
Weaver, Leslie Berg. 19th
Edition. 2022. W. W. Norton
& Company (some Figures)
Punt • Stranford • Jones • Owen
Kuby Immunology
EIGHTH EDITION
CHAPTER 15
Allergy, Hypersensitivities, and Chronic Inflammation
Copyright © 2019 by W. H. Freeman and Company

Four types of
hypersensitivity
reactions
https://www.youtube.com/watch?v=2tmw9x2Ot_Q https://www.youtube.com/watch?v=kLaUz58CBMc
http://highered.mheducation.com/sites/ http://highered.mheducation.com/sites/
0072507470/student_view0/chapter22/ 0072507470/student_view0/chapter22/
animation__ige_mediated__type_1__h animation__cytotoxic__type_ii_hyperse
ypersensitivity__quiz_1_.html nsitivity_.html
Type IV not available
https://www.youtube.com/watch?v=0T_SAXyMs_c
http://highered.mheducation.com/sites/007250 http://highered.mheducation.com/site
7470/student_view0/chapter22/animation__im s/0072507470/student_view0/chapter
mune_complex_type_3_hypersensitivity.html 22/animation__delayed__type_iv__h
ypersensitivity.html
Allergy: A type I hypersensitivity reaction
• IgE antibodies are responsible for type I hypersensitivity
• Allergies are initiated by an interaction between an IgE

antibody and a multivalent antigen
• Free circulating IgE is usually very, very low in concentration

in blood serum
• This hampered studies on the antibody for a period of time
• Many allergens can elicit a type I response
• Healthy individuals make IgE only in response to parasitic
infections
• Atopic individuals produce IgE against common environmental

Ags
• Most are proteins or glycoproteins
• Most possess many antigenic sites (epitopes) per molecule

• Often have intrinsic enzymatic properties
• May contain potential PAMPs, stimulating innate immunity
• May enter mucosal tissues at very low concentrations, inducing IgE-stimulating
TH2 responses
Table 15-1, Common allergens associated with type I hypersensitivity, Page 551
Plant pollens Drugs

Rye grass Penicillin
Ragweed Sulfonamides
Timothy grass Local anesthetics
Birch tree Salicylates
Foods Insect products
Nuts Bee venom
Seafood Wasp venom
Eggs Ant venom
Peas, beans Cockroach calyx
Milk Dust mites
Other allergens
Animal hair and dander
Latex
Mold spores
• IgE antibodies act by cross-
linking Fcε receptors on the
surfaces of innate immune
cells
• Abs not harmful by themselves
• Granule contents released

include histamine, heparin,
proteases, leukotrienes,
prostaglandins, chemokines
• Mediators act on surrounding

tissues and cells to cause
symptoms
• IgE antibodies act by cross-linking
Fcε receptors on the surfaces of
innate immune cells
• The high-affinity IgE receptor, FcεRI
• Responsible for most allergy symptoms
• Mast cells and basophils constitutively

express
• The low-affinity IgE receptor, FcεRII

• Regulates production of IgE by B cells
• IgE antibodies act by cross-linking
Fcε receptors on the surfaces of
innate immune cells
• The high-affinity IgE receptor, FcεRI
• Linking receptors trigger Lyn-mediated

phosphorylation of ITAMs
• Triggers PKC and MAPK pathways,

leading to allergic effects
• The low-affinity IgE receptor, FcεRII

Allergy: A type I
hypersensitivity
reaction
• IgE receptor signaling is tightly regulated
• Coclustering with inhibitory receptors

• Mast cells express both FcεR1 (activating) and FcγRIIB (inhibiting) Ig
receptors
• If a cell binds IgE and IgG, the inhibiting signal induced by IgG binding wins
• In part why inducing IgG in atopic individuals (“allergy shots”) is effective
• Inhibition of downstream signaling molecules

• Lyn can also phosphorylate ITIMs on FcγRIIB, inhibiting signaling
• Signaling through FcεR1 activates E3 ubiquitin c-Cbl

• This targets Lyn, Syk, and even FcεR1 for degradation by proteasomes
Table 15-2, Principal mediators involved in type I hypersensitivity, Page 558
Mediator Effects
Primary
Histamine, heparin Increased vascular permeability; smooth muscle contraction
Serotonin (rodents) Increased vascular permeability; smooth muscle contraction
Eosinophil chemotactic factor (ECF-A) Eosinophil chemotaxis
Neutrophil chemotactic factor (NCF-A) Neutrophil chemotaxis
Proteases (tryptase, chymase) Activate matrix metalloproteinases, which break down extracellular matrix
proteins, causing tissue damage (e.g. degradation of blood vessel
basement membrane); generation of complement split products
Secondary
Platelet-activating factor Platelet aggregation and degranulation; contraction of pulmonary smooth
muscles
Leukotrienes (slow reactive substance of Increased vascular permeability; contraction of pulmonary smooth
anaphylaxis, SRS-A) muscles; bronchial mucus secretion
Prostaglandins Vasodilation; contraction of pulmonary smooth muscles; platelet
aggregation; bronchial mucus secretion
Bradykinin Increased vascular permeability; smooth muscle contraction
Cytokines
IL-1 and TNF-α Systemic anaphylaxis; increased expression of adhesion molecules on
venous endothelial cells
IL-4 and IL-13 Induction of TH2 cells, increased IgE production
IL-3, IL-5, IL-6, IL-8, IL-9, IL-10, TGF-β, Various effects (see text)
and GM-CSF
• Innate immune cells produce molecules responsible for type I
hypersensitivity symptoms
• Histamine
• Formed by decarboxylation of histidine amino acid
• Binds to one of four possible histamine receptors (H1-H4)

• H1 binding induces contraction of intestinal and bronchial smooth muscles, increased
permeability of venules, and mucous secretion
• H2 binding increases vasopermeability and vasodilation, stimulates exocrine glands, and
increases stomach acid; also suppresses degranulation of mast cells/basophils in a
negative feedback loop
• H3 less involved in type 1; modulates neurotransmitter activity in CNS
• H4 mediates mast cell chemotaxis
• Innate immune cells produce molecules responsible for
type I hypersensitivity symptoms
• Leukotrienes and prostaglandins
• Secondary mediators — formed when membrane phospholipids are

enzymatically cleaved
• Active at nanomole levels (1000× more effective than histamine at

inducing bronchoconstriction!)
• Also more potent stimulators of vascular permeability and mucous secretion
• Considered to be a major cause of asthma symptoms
• Cytokines and chemokines
• Mast cells and basophils release several of these signaling molecules
• IL-4 and IL-13 stimulate TH2 responses to increase IgE production by B cells
• IL-5 recruits and activates eosinophils
• TNF-α may contribute to shock in systemic anaphylaxis
• CXCL-8 (= IL-8) acts as a chemotactic factor, attracting other cells
• GM-CSF stimulates production and activation of myeloid cells, e.g.,

granulocytes
• Type I hypersensitivities are characterized by early and late
responses
• Early responses occur within minutes of allergen exposure

• Mediated by mast cell granule release of histamine, leukotrienes, and
prostaglandins
• Late responses, hours later, a result of recruited cells

• Cytokines released from mast cells increase expression of chemokines and
CAMs on endothelium facilitating influx of neutrophils, eosinophils, and TH2 cells
• Eosinophils play a large role in late-phase recruiting neutrophils and
degranulation
• A third phase has been described involving basophils and fibroblasts

Allergy: A type I
hypersensitivity
reaction
• There are several categories of type I hypersensitivity reactions
• Systemic anaphylaxis
• Often initiated by an injected or gut-absorbed allergen, e.g., bee sting venom,
penicillin, seafood, nuts
• Symptoms include:
• Labored respiration
• Precipitous drop in blood pressure leading to anaphylactic shock
• Contraction of smooth muscles leading to bronchiolar constriction
• May lead to death by asphyxiation
• Epinephrine is the immediate treatment

• There are several categories of type I hypersensitivity
reactions
• Localized hypersensitivity reactions
• Pathology is limited to a specific tissue or organ
• Includes allergic rhinitis (hay fever), allergic conjunctivitis, asthma, atopic

dermatitis (eczema), atopic urticaria (hives), and food allergies
• Symptoms result from release of mediators in immediate exposure area

• There are several categories of type I hypersensitivity

reactions
• Food allergies: a common type of atopy on the rise

• Food allergens are often water-soluble glycoproteins stable to
heat, acid, and proteases
• Can cause vomiting and diarrhea due to smooth muscle contraction

and gut vasodilation
Table 15-3, Immune basis for food allergy reactions, Page 563a
Disorder Symptoms Common triggers Notes about mechanism

IgE mediated (acute)
Skin effects: hives Redness, swelling triggered Multiple foods (e.g., milk, Allergen, IgE antibody, and
(urticaria), itching, by ingestion or skin contact egg, wheat, soy, peanut, mast cell mediated
angioedema tree nuts, shellfish, fish)
Oral allergy Itchiness, swelling of mouth Multiple foods Allergen, IgE antibody, and
mast cell mediated. Inhaled
pollens may induce IgE that
cross-reacts with food proteins
Gastrointestinal effects Nausea, vomiting, intestinal Multiple foods Allergen, IgE antibody, and
pain mast cell mediated
Wheezing, asthma, Bronchial constriction, mucus Inhalation of aerosolized Allergen, IgE antibody, and
rhinitis production food proteins mast cell mediated
Anaphylaxis Rapid, multiorgan Peanuts, tree nuts, fish, Response to systemic
inflammation that can result in shellfish, milk distribution of allergen and IgE
cardiovascular failure antibodies
Exercise-induced As above, but occurs when Wheat, shellfish, celery May be due to changes in gut
anaphylaxis one exercises after eating absorption associated with
trigger foods exercise
Table 15-3, Immune basis for food allergy reactions, Page 563b
Disorder Symptoms Common triggers Notes about mechanism

IgE and cell mediated
(chronic)
Atopic dermatitis Rash (often in children) Egg, milk, wheat, soy Skin TH2 cells may contribute
Gastrointestinal Pain, weight loss, edema, Multiple foods Eosinophil mediated
inflammation and/or obstruction
Cell mediated
(chronic)
Intestinal inflammation Most often seen in infants: Cow’s milk (directly or via T cells and TNF-α have been
brought about by diarrhea, poor growth, and/or breast milk), soy, grains, implicated
dietary protein (e.g., bloody stools egg
enterocolitis, proctitis)
• Environmental and genetic basis for type I hypersensitivity
• Environmental factors include air pollution through to diet, and genetics

both influence susceptibility to allergies
• The hygiene hypothesis has been advanced to explain increases in

allergy incidence
• Proposes that exposure to some pathogens early in life provides a better T-

cell balance
• Avoids dominance of TH2 subset, which promotes IgE production by B cells
(stimulating allergic responses)
• May explain why countries with improved hygiene are experiencing increases
in asthma and allergy rates
• Induction of allergic responses
• Food allergy initial sensitization takes place through the skin

• Infants with eczema and children deficient in filaggrin support the hypothesis
• Skin epithelial cells produce innate cytokines that affect DCs and induce
allergen-specific TH2 cells, which trigger B-cell isotype switch to IgE
• Circulating IgE Ab carried in blood to intestinal tissue
• Intestinal epithelial, ILC2, TH2, and TH9 cells are activated by binding IgE to
produce cytokines that recruit, support, activate mast cells and basophils
• Mediators released that cause symptoms of food allergies

• Diagnostic tests and treatments
are available for type I
hypersensitivity reactions
• Skin testing is commonly used

• Cheap, safe
• Inject small quantities of known
allergens under skin
• Swelling and redness (resulting
from local mast cell degranulation)
indicate allergic response
• May also assess and quantify total

or allergen-specific IgE serum
levels using ELISA or Western blot
methods (unusual)
• Diagnostic tests and treatments are available for type I
• Antihistamines, leukotriene antagonists, and inhalation corticosteroids
• Antihistamines bind and block H1 receptors on target cells

• First-generation drugs can cross into central nervous system and cause side effects
• Second-generation drugs have fewer side effects
• Leukotriene antagonists work in a manner similar to antihistamines
• Inhalation corticosteroids inhibit innate immune cell activity in airways, treating

asthma
• Diagnostic tests and treatments are available for type I hypersensitivity reactions
• Desensitization immunotherapy
• Repeated low-dose exposures may induce a TREG cell increase and their cytokines
• May also induce TH1 and TREG cells where TH1 cytokines induce competitive IgG subtypes
switching from IgE to IgG4
• TREG cytokines downregulate TH2 response inhibiting recruitment of basophils and eosinophils
• Oral immunotherapy consists of feeding children increasing amounts of the food allergen(s)
• Anti-IgE antibodies that bind and inhibit the allergen-specific IgE from binding to mast cell FcεR
molecules
Antibody-mediated (type II) hypersensitivity reactions
• Transfusion reactions are an example of type II

hypersensitivity
• Involve Ab-mediated destruction of cells by non-IgE Ab
• Blood group Ag are carbohydrates
• Adults possess antibodies to the blood type they do NOT have
• If they receive a transfusion of the “wrong” type of blood, their antibodies will
quickly attach to the donor blood cells and trigger complement proteins
• The degraded RBC components can build to toxic levels
• Hemolytic disease of the newborn is caused by type II

reactions
• Develops when maternal IgG Ab specific to the expressed RhD

allele crosses the placenta
• Destroys fetal RBCs by binding and activating complement

• Can be fatal, but can be treated by intrauterine blood-exchange transfusion and
other methods
• Build-up of toxic RBC components can result

• Can be alleviated by exposure to UV light
• Hemolytic anemia can be drug induced
• Some drugs can adsorb nonspecifically to proteins on RBC

membranes
• These drug-protein complexes may stimulate antibody production
• Antibodies then bind to RBCs when the drug is present, stimulating

complement-mediated destruction
• Penicillin can induce all four types of hypersensitivities under the correct
circumstances for each
Table 15-4, Penicillin-induced hypersensitivity reactions, Page 575
Type of reaction Antibody or lymphocyte induced Clinical manifestations

I IgE Urticaria, systemic anaphylaxis
II IgM, IgG Hemolytic anemia
III IgG Serum sickness, glomerulonephritis
IV T cells Contact dermatitis
Immune complex-mediated (type III)
hypersensitivity
• Immune complexes can damage various tissues
• If immune complexes aren’t cleared effectively, they may deposit

in tissues
• May trigger release of inflammatory mediators and vasoactive mediators

• Proteases released may damage connective tissues
• Clots may form as complexes activate platelets
• Symptoms include fever, rashes, joint pain, lymph node enlargement,

and proteinuria
• Vasculitis if in blood vessel
• Glomerulonephritis if in kidney
• Arthritis if in joints
Immune complex-mediated (type III)
hypersensitivity
• Immune complex-mediated hypersensitivity can resolve
spontaneously
• Eventually, complexes ARE cleared so long as Ag eventually

goes away
• Autoantigens can be involved in immune complex-

mediated reactions
• And Ag can’t completely go away in such a case

Table 15-5, Examples of conditions involving type III hypersensitivity reactions, Page 576
Autoimmune diseases
Systemic lupus erythematosus
Rheumatoid arthritis
Drug reactions
Allergies to penicillin and sulfonamides
Infectious diseases
Poststreptococcal glomerulonephritis
Meningitis
Hepatitis
Mononucleosis
Malaria
Trypanosomiasis
Immune complex-mediated
(type III) hypersensitivity
• Arthus reactions are localized type
III hypersensitivity reactions
• An inflammatory reaction induced by

injection of an Ag in an individual with
high levels of circulating Ab specific to it
• Swelling and localized bleeding at

injection site
• Peaks 4–10 hours post injection

• May take place after a rapid, localized
type I reaction to an insect bite
• May develop in lungs after inhalation of
Ag, e.g., farmer’s lung from moldy hay
Delayed-type (type IV) hypersensitivity (DTH)
• Purely cell mediated rather than Ab mediated
• Initiated by T cells
• Requires a delay for the reaction to develop
• Characterized by recruitment of macrophages at inflammation site
• Poison ivy contact dermatitis is the most common example

Table 15-6, Intracellular pathogens and contact antigens that induce delayed-type (type IV) hypersensitivity, Page 578
Intracellular bacteria Intracellular viruses

Mycobacterium tuberculosis Herpes simplex virus
Mycobacterium leprae Variola (smallpox)
Brucella abortus Measles virus
Listeria monocytogenes
Intracellular fungi Contact antigens
Pneumocystis carinii Picryl chloride
Candida albicans Hair dyes
Histoplasma capsulatum Nickel salts
Cryptococcus neoformans Poison ivy
Poison oak
Intracellular parasites
Leishmania sp.
• The initiation of a type IV DTH

response involves
sensitization by an antigen
• Initial exposure triggers

production of a T-cell response
• Often of the CD4+ TH1 subset
• Takes 1–2 weeks of time
• The effector phase of a classical

DTH response is induced by
second exposure to a
sensitizing Ag
• Second exposure induces

production of TH1 inflammatory
cytokines
• These recruit and help activate

macrophages
• A prolonged activation of
macrophages leads to granuloma
formation
• The effector phase of a

classical DTH response is
induced by second exposure
to a sensitizing Ag
• A prolonged inability to clear Ag

(as seen in TB) can result in
formation of destructive
multinucleate giant cell and
granulomas
• The DTH reaction can be detected by a skin test
• By injecting a small amount of Ag under the skin
• If a red, slightly swollen, firm lesion develops in 48–72 hours, the test is positive
• This indicates the individual has a population of sensitized T H1 cells against the Ag
• This does NOT indicate if an active infection is occurring or if the individual already
overcame an infection (leaving memory cells)
• Commonly used in the United States to test for tuberculosis exposure

Delayed-type (type IV)
hypersensitivity (DTH)
• Contact dermatitis
• Sensitization can occur if a reactive

chemical compound binds to skin
proteins
• Modified proteins are then presented

to T cells
• Could be induced by cosmetics,

pharmaceuticals, industrial chemicals,
metal ions, poison ivy, poison oak
• Can cause strong cell-mediated

responses against skin cells, inducing
blisterlike lesions and rashes
• Contact dermatitis: Poison Oak
• Sensitization can occur if a reactive chemical compound binds to skin

proteins
• Urushiol oxidation in skin allows it to bind to skin proteins

• Modified proteins taken up by DCs carried to regional lymph node where degraded and
presented on MHC class II
• MHC class II peptides induce TH1 formation
• TH1 cells return to skin, release cytokines that activate macrophages
• Macrophages release inflammatory cytokines, lytic enzymes, and ROS species

causing tissue damage
Delayed-type (type IV)
hypersensitivity (DTH)
Chronic inflammation
• Inflammation doesn’t always resolve in a short period of time; it may last
indefinitely, contributing to numerous other problems
• Infectious conditions can lead to tissue damage
• Physical damage to tissues can release DAMPs that induce inflammatory mediators
• Obesity can result in a chronic inflammation due to visceral adipocyte stimulation to

release inflammatory cytokines
• Diabetes can result in chronic inflammation as a consequence of inflammatory

cytokines inhibiting downstream events at the insulin receptor
• Cytokines released during chronic inflammation can induce widespread tissue

scarring leading to organ dysfunction contributing to tumor development
• Infections can cause chronic inflammation

• Continual microbial invasion can induce chronic inflammation
• Gum disease
• Unhealed wounds
• Failure of tolerance mechanisms to gut microbes
• Some microbes are ineffectively cleared, inducing chronic

inflammation
• Certain fungal and mycobacterial infections
• There are noninfectious causes of chronic inflammation
• Damage-associated molecular patterns (DAMPs)
• Self-Ag released by certain conditions associated with damage

• Tumors
• Autoimmune diseases
• Atherosclerosis and heart disease
• Obesity
• Each capable of inducing long-term inflammation

• Obesity is associated with chronic inflammation
• Visceral adipocytes are secretors of proinflammatory

cytokines
• TNF-α
• IL-6
• May trigger other disease states associated with chronic

inflammation
• Chronic inflammation can cause systemic
disease
• Chronic inflammation and insulin resistance
• TNF-α/IL-6 induce signaling cascades that inhibit

ability of insulin receptors to function
• Greater obesity linked to greater risk of Type 2

diabetes
• Lose the fat, get insulin response back (sometimes)
• Chronic inflammation and susceptibility to other

diseases
• Inflammation can drive blood vessel production and

wound repair mechanisms
• Too much can lead to excessive tissue scarring
(fibrosis)
• Could also promote tumor formation and enhance
angiogenesis
Summary
• Hypersensitivities are examples of a good thing gone wrong
• Each type represents an immune response initiating harm rather

than help
• Each has slightly different triggers and outcomes, but each is

potentially very serious
• Understanding each type allows clinicians to intervene more

effectively, alleviating symptoms
Punt • Stranford • Jones • Owen
Kuby Immunology
EIGHTH EDITION
CHAPTER 16
Tolerance and Autoimmunity
Copyright © 2019 by W. H. Freeman and Company

Establishment and maintenance of
tolerance
• Tolerance: prevention of an
immune response against self
structures
• Central tolerance – deletion of

lymphocytes before they
mature
• Takes place in generative

lymphoid organs
tolerance
• Tolerance: prevention of an
immune response against self
structures
• Peripheral tolerance – either

renders self-reactive
lymphocytes nonresponsive or
actively generates inhibiting
lymphocytes
• Occurs outside bone marrow and

thymus
tolerance
• Antigen sequestration is one means to protect self-
antigens from attack
• Anterior chamber and lens of eye lack lymphatic drainage

• Also possess tissue-specific Ag that are isolated from interaction
with immune cells
• Damage to such areas may expose their Ag to immune

responses, initiating damage potential
Janeway´s
Immunobiology 10th
Edition
tolerance
• Central tolerance limits development of autoreactive T and
B cells
• High affinity for self-Ag results in induction of apoptosis in B and T

cells
• B cells have been shown to undergo receptor editing
• A second V gene segment is rearranged into the first rearrangement

• Often, this results in rendering the receptor inactive
• Occasionally, a new non-self-specific receptor can be generated
tolerance
• Peripheral tolerance regulates autoreactive cells in the
circulation
• Regulatory CD4+ T cells
• Can be generated naturally in the thymus (nTREG cells) or in the periphery

following Ag induction (iTREG cells)
• Still engage Ag-MHC class II complexes through TCR

• Downregulate responses when they do so!
• May help to shut down allergic responses as well
tolerance
• Peripheral tolerance regulates autoreactive cells in the
circulation
• Work via contact dependent and independent mechanisms

• Dependent mechanisms occur as TREG cells express high levels of inhibitory
CTLA-4 molecules
• Independent mechanisms rely upon secretion of cytokines (IL-10, TGF-β,
IL-35) into the surrounding area, shutting down nearby cells’ responses
tolerance
tolerance
• Peripheral tolerance regulates
autoreactive cells in the circulation
• An interesting “bystander
suppression” effect can occur
• A TREG that interacts with an APC can

suppress T cells that engage separate
Ag-MHC class II complexes on the APC
surface
• This phenomenon is known as linked

suppression
tolerance
• Peripheral tolerance regulates autoreactive cells in the circulation
• Complex and still under investigation
• Apparently are NOT generated in the thymus but instead in the periphery during CD8+ T-cell
activation induction events
• Appear after Ag-MHC class I stimulation in the presence of TGF-β cytokine
• Most likely use a range of mechanisms (similar to CD4+ TREG cells) to suppress activity
• Lysis of APCs
• Inhibition of APC function
• Regulation of effector cells that bind the same Ag
tolerance
• Peripheral tolerance regulates autoreactive cells in the circulation
• Regulatory B cells (BREGs) may exist, producing IL-10 as an inhibitor

of adaptive immunity – still being studied/clarified
• Myeloid-derived suppressor cells (MDSCs) may secrete inhibitory

compounds such as IL-10, produce indoleamine 2,3-dioxygenase
(IDO), arginase-1, and inducible nitric oxide synthase (iNOS) to
negatively regulate autoimmunity (acting as immune-inhibiting APCs)
• These cells may also express immunosuppressive surface markers such as PD-
L1
Autoimmunity
• Caused by the failure of tolerance processes
• May be organ specific or systemic
• May involve antibodies, T cells, immune complexes, or any

combination of elements
Table 16-1, Some autoimmune diseases in humans, Page 603a
Disease Self-antigen/Target gene Immune effector

ORGAN-SPECIFIC AUTOIMMUNE
DISEASES
Addison’s disease Adrenal cells autoantibodies
Autoimmune hemolytic anemia RBC membrane proteins autoantibodies
Goodpasture’s syndrome Renal and lung basement membranes autoantibodies
Graves’ disease Thyroid-stimulating hormone receptor autoantibodies (stimulating)
Hashimoto’s thyroiditis Thyroid proteins and cells TH1 cells, autoantibodies
Idiopathic thrombocytopenic purpura Platelet membrane proteins autoantibodies
Type 1 diabetes mellitus Pancreatic beta cells TH1 cells, autoantibodies
Myasthenia gravis Acetylcholine receptors autoantibodies (blocking)
Myocardial infarction Heart autoantibodies
Pernicious anemia Gastric parietal cells; intrinsic factor autoantibodies
Poststreptococcal glomerulonephritis Kidneys Immune complexes
Spontaneous infertility Sperm autoantibodies
Table 16-1, Some autoimmune diseases in humans, Page 603b
Disease Self-antigen/Target gene Immune effector
SYSTEMIC AUTOIMMUNE
DISEASES
Ankylosing spondylitis Vertebrae Immune complexes
Multiple sclerosis Brain or white matter TH1 cells and TC cells,
autoantibodies
Rheumatoid arthritis Connective tissue, IgG autoantibodies, immune complexes
Scleroderma Nuclei, heart, lungs, gastrointestinal autoantibodies
tract, kidneys
Sjögren’s syndrome Salivary glands, liver, kidneys, thyroid autoantibodies
Systemic lupus erythematosus (SLE) DNA, nuclear protein, RBC, and autoantibodies, immune complexes
platelet membranes
lmmune dysregulation, Multiorgan/loss of FoxP3 gene Missing regulatory T cells
polyendocrinopathy, enteropathy, X-
linked (IPEX) syndrome
Autoimmune polyendocrine syndrome Multiorgan/loss of AIRE gene Defective central tolerance
type 1 (APS-1)
Janeway´s
Immunobiology 10th
Edition
Janeway´s
Immunobiology 10th
Edition
Autoimmunity
• Several animal autoimmune disease models exist
• These allow for safer and ethical characterization of related

human illnesses but are not perfect
Table 16-2, Experimental animal models of autoimmune diseases, Page 604a
Disease
Possible human disease Inducing
Animal model transferred by T
counterpart antigen
cells
SPONTANEOUS
AUTOIMMUNE DISEASES
Nonobese diabetic (NOD) Type 1 diabetes (T1D) Unknown Yes
mouse
(NZB × NZW) F1 mouse Systemic lupus Unknown Yes
erythematosus (SLE)
Obese-strain chicken Hashimoto’s thyroiditis Thyroglobulin Yes
Table 16-2, Experimental animal models of autoimmune diseases, Page 604b
Disease
Possible human
Animal model Inducing antigen transferred by T
disease counterpart
cells
EXPERIMENTALLY INDUCED
AUTOIMMUNE DISEASES*
Experimental autoimmune Myasthenia gravis Acetylcholine Yes
myasthenia gravis (EAMG) receptor
Experimental autoimmune Multiple sclerosis (MS) Myelin basic protein Yes
encephalomyelitis (EAE) (MBP); proteolipid
protein (PLP)
Autoimmune arthritis (AA) Rheumatoid arthritis Mycobacterium Yes
(RA) tuberculosis
(proteoglycans)
Experimental autoimmune Hashimoto’s thyroiditis Thyroglobulin Yes
thyroiditis (EAT)
Autoimmunity
• Some autoimmune diseases target specific organs
• Hashimoto’s thyroiditis
• Autoantibodies and sensitized TH1 cells specific for thyroid Ag are produced
• More common in women
• Ab produced interferes with iodine uptake

• Decreases thyroid function leading to hypothyroidism
• Induces DTH response in the thyroid

• Inflammation results in goiter — visible enlargement of the thyroid gland
Autoimmunity
• Type 1 diabetes mellitus
• Affects almost 2:1000 children in the US
• Mostly seen in youths under age 14
• Caused by autoimmune attack against

insulin-producing beta cells in
pancreas
• CTLs infiltrate the pancreas and activate
macrophages
• This is followed by cytokine release and
production of autoantibodies, which may
activate complement or ADCC activities by
NK cells
• Eventual DTH response releases
destructive enzymes
Janeway´s
Immunobiology 10th
Edition
Autoimmunity
• Myasthenia gravis
• Autoantibodies produced that bind
acetylcholine receptors on motor
end plates of muscle
• Block the normal binding of

acetylcholine, induce complement-
mediated lysis
• Result in progressive weakening of

skeletal muscles
• Treatments are aimed at increasing

acetylcholine levels, decreasing Ab
production, and/or removing Ab
Autoimmunity
• Systemic lupus erythematosus (SLE)
• More common in women (9:1 ratio)
• Symptom onset typically between 20-40 yoa
• More frequent in African American and

Hispanic women than Caucasians
• Auto-Ab against DNA, histones, other self

structures
• Can be detected by indirect
immunofluorescence
• Symptoms result from specificity of Ab

produced:
• Fever, weakness, arthritis, skin rashes, and
kidney dysfunction
• Type III hypersensitivity reactions often induce
damage
Janeway´s
Immunobiology 10th
Edition
Autoimmunity
• Multiple sclerosis
• Occurs in women two to three times more frequently than in men
• Most common cause of neurologic disability associated with disease in

Western countries
• More common in the Northern Hemisphere but also has an unresolved genetic
component leading to increased risk
• Some data indicate certain infections may also predispose a person to MS
• Autoreactive T cells form inflammatory lesions along myelin sheaths around

nerve fibers in the brain and spinal cord
• Breakdown leads to a range of symptoms, from numbness to paralysis and loss of vision
Janeway´s
Immunobiology 10th
Edition
Autoimmunity
• Rheumatoid arthritis
• Often diagnosed between 40 and 60 years of age
• More frequent in women
• Major symptom is chronic joint inflammation

• Rheumatoid factors are often produced
• Auto-Ab reactive with determinants in the Fc region of
IgG
• Form immune complexes and activate complement
cascades
• Treatments include nonspecific anti-inflammatory

drugs and corticosteroids
• More specific anticytokine antibodies have also been
introduced
Janeway´s
Immunobiology 10th
Edition
Janeway´s
Immunobiology 10th
Edition
Autoimmunity
• Systemic autoimmunity due to disruptions in immune regulation
• Two classic examples:

• Autoimmune polyendocrine syndrome type-1 (APS-1) (previously APECED)
• Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome
• Both are monogenic disorders (caused by a single gene)

• APS-1 is caused by mutations in the AIRE gene
• IPEX is caused by mutations in the FoxP3 gene
• Impact multiple organs
• Display the same range of immunopathologies (endocrine dysfunction,

autoimmunity, and primary immune deficiency)
Autoimmunity
• Both intrinsic and extrinsic factors can favor susceptibility to
autoimmune disease
• The roles of genes in susceptibility to autoimmunity
• Certain MHC genes linked to specific autoimmune disorders, for example
• HLA-B27 expression = 90× more likely to develop ankylosing spondylitis, an

inflammatory disease of vertebral joints
• Mutations in AIRE and FoxP3 genes result in particular immunodeficiencies that affect
central and peripheral tolerance
• Genes that encode cytokines connected to TH17 function (IL-12, IL-17, and IL-23)
Table 16-3, Examples of genetic associations with autoimmune disease, Page 611
Cytokines, their
C-type Innate immune Adhesion and Antigen processing
Disease receptors and
lectin response costimulation and presentation
regulators
Type 1 diabetes CLEC16A IL-2R CTLA4 VNTR-Ins, PTPN22
(T1D)
Rheumatoid DCIR STAT4 REL, C5-TRAFI CD40 PTPN22, MHC2TA
arthritis (RA)
Ankylosing IL-1A, IL-23R KIR complex ERAP1
spondylitis (AS)
Multiple sclerosis CLEC16A IL-2RA, IL-7R CD40
(MS)
Systemic lupus STAT4, IRF5 TNFAIP3 TNFSF4 PTPN22
erythematosus
(SLE)
Crohn’s disease CLEC16A IL-23R NOD2, NCF4 TNFSF15 PTPN2
Autoimmunity
autoimmune disease
• Environmental factors favoring the development of autoimmune

disease
• Diet differences may lead to gut microflora differences
• Different geographic areas may have different endemic diseases
• These differences may account for biased representation of

certain autoimmune disorders in populations — an area of active
study
Autoimmunity
autoimmune disease
• The role of certain T helper cell types in autoimmunity
• Some evidence for autoreactive TH1 cells secreting IFN-γ and assisting
development of multiple sclerosis
• Also some evidence for elevated IL-17 levels in rheumatoid arthritis and
psoriasis patients, indicating a role for TH17 cells in these autoimmune
diseases
Autoimmunity
• Several possible mechanisms have been proposed for the
induction of autoimmunity
• Induction may be multifactorial

• Combining a series of triggering events that cross an individual’s
systems of tolerance over a threshold
• Infections and molecular mimicry
• Infections that induce genetic changes
• Damage/stress events that expose sequestered Ag
• Foods that alter gut microbial balance, promoting chronic inflammation and
Janeway´s
Immunobiology 10th
Edition
Table 16-4, Common proinflammatory environmental factors in autoimmune diseases, Page 613
Group Examples Disease association examples

Infection Viral Type 1 diabetes
Bacterial Reiter’s syndrome
Fungal Autoimmune polyendocrine syndrome type 1 (APS-1)
Toxins Smoking Rheumatoid arthritis
Fabric dyes Scleroderma
Iodine Thyroiditis
Stress Psychological Multiple sclerosis, systemic lupus erythematosus (SLE)
Oxidative, metabolic Rheumatoid arthritis
Ultraviolet light SLE
Endoplasmic reticulum Ulcerative colitis
(ER) stress
Food Gluten Celiac disease
Breastfeeding Type 1 diabetes
cessation
Gastric bypass Spondyloarthropathy
Autoimmunity
• Autoimmune diseases can be treated by general or pathway-
specific immunosuppression
• Broad-spectrum therapies
• Early methods; usually simply reduce symptoms
• Strong anti-inflammatory drugs that inhibit lymphocyte proliferation or kill the

cells
• General toxicity is a negative side effect
• Also predisposes individuals to uncontrolled infections
• Can promote development of cancer by removing antitumor T and NK cells
• Organ removal may also alleviate some symptoms in certain cases

Autoimmunity
• Strategies that target specific cell types (continued)
• If the disease is caused by immune complexes, targeting B cells can be
effective
• Monoclonal Ab against CD20 used in RA cases
• T-cell targeting therapies are used more often because the cells are
usually directly pathogenic or provide help to B cells
• Early efforts targeting CD3 molecules proved ineffective, but other drugs
targeting TCR signaling work well
• As we learn more about specific T-cell subsets, like TH17, and their
biology, we learn better ways to inhibit their specific helper T cell pathways
Autoimmunity
• Autoimmune diseases can be treated by general or pathway-specific
immunosuppression
• Therapies that block steps in the inflammatory process
• Drugs that block TNF-α are used to treat RA, psoriasis, and Crohn’s disease
• IL-1 receptor antagonist can be used against RA, as can Ab against IL-6 receptor and IL-15
• Statins lower serum levels of C-reactive protein, an indicator of inflammation, and reduce
proinflammatory cytokine levels
• Compounds that block chemokine or adhesion molecule signals prevent movement of

lymphocytes into areas of inflammation
• FTY720, an analog of S1P (sphingosine 1-phosphate)
• Fig. 14-8 Kuby Immunology. Lymphocyte exit the lymph node through portals in
the cortical and medullary sinus.
• If naïve lymphocytes do not find antigen within a certain period, they up-regulate S1PR1 and
enter efferent lymphatic vessels from the cortex (B cells) and medulla (T cells)
Autoimmunity
• Autoimmune diseases can be treated by general or

pathway-specific immunosuppression
• Strategies that interfere with costimulation

• Formation of a fusion protein
• Extracellular domain of CTLA-4 and human IgG1 constant region
• Abatacept (Orencia) approved for RA treatment blocks CD80/86 on APCs from
engaging with CD28 on T cells, inhibiting costimulation
• Binds to T cells, tricking them into an arrangement that inhibits stimulation

Autoimmunity
• Autoimmune diseases can be treated by general or
pathway-specific immunosuppression
• Antigen-specific immunotherapy
• The Holy Grail — stimulate tolerance to the auto-Ag, restoring balance
• Glatiramer acetate has been used to treat MS
• Four basic amino acids found in MBP
• Selectively increases TREG cells, modulating APC function
• Early stage development for T1D treatment shows promise

• Nanoparticles coated with proinsulin, a target in type 1 diabetes, delivers a
tolerogenic signal to APCs
Table 16-5, Drugs currently approved by the FDA or undergoing clinical trials to treat autoimmune disease or suppress the
immune response, arranged according to mechanism of action, Page 615a
Name Brand name Mechanism of action Target disease/Syndrome

T- OR B-CELL –
DEPLETING AGENTS
Lymphocyte immune ATGAM (horse), Depleting horse/rabbit polyclonal Renal transplant rejection;
globulin (horse), anti- Thymoglobulin antithymocyte antibody aplastic anemia
thymocyte globulin (rabbit) (rabbit)
Muromonab (OKT3) Orthoclone OKT3 Mouse antihuman CD3 mAb; Acute transplant rejection;
depleting graft-versus-host disease
(GvHD)
Zanolimumab HuMax-CD4 Human anti-CD4 mAb, partially Rheumatoid arthritis (RA)
depleting
Rituximab (IDEC-C2B8) Rituxan Chimeric anti-CD20 mAb; RA
depleting
TARGETING
TRAFFICKING/ ADHESION
Fingolimod (FTY720) Gilenya S1P receptor agonist; stimulating Relapsing/remitting multiple
sclerosis (MS); renal
transplant rejection
immune response, arranged according to mechanism of action, Page 615b

TARGETING TCR
SIGNALING
Cyclosporin A Gengraf, Neoral, Calcineurin inhibitor Transplant rejection; active RA;
Sandimmune severe plaque psoriasis
Tacrolimus (FK506) Prograf (systemic), Calcineurin inhibitor Transplant rejection; atopic
Protopic (topical) dermatitis; ulcerative colitis
(UC); RA; myasthenia gravis;
GvHD
TARGETING
COSTIMULATORY AND
ACCESSORY
MOLECULES
Abatacept (BMS-188667) Orencia Fc fusion protein with RA; lupus nephritis;
extracellular domain of CTLA-4; inflammatory bowel disease
blocks CD28-CD80/86 (IBD); juvenile idiopathic arthritis
interaction (JIA)
immune response, arranged according to mechanism of action, Page 615c
Belatacept (BMS-224818, Nulojix Same as Abatacept, higher affinity Transplant rejection

LEA29Y)
TARGETING
CYTOKINES/CYTOKINE
SIGNALING
Sirolimus Rapamune mTOR inhibitor Renal transplant rejection; GvHD
Summary
• This chapter covered several diverse but related topics
• Tolerance — understanding tolerance mechanisms is critical

to understanding
• Autoimmunity — where tolerance mechanisms fail

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Imunopatologia

3º Ano Mestrado Integrado em Medicina

Copyright © 2019 by W. H. Freeman and Company

Type IV not available

• IgE antibodies are responsible for type I hypersensitivity

• Allergies are initiated by an interaction between an IgE

• Free circulating IgE is usually very, very low in concentration

• Atopic individuals produce IgE against common environmental

• Most are proteins or glycoproteins

• Most possess many antigenic sites (epitopes) per molecule

Plant pollens Drugs

• Abs not harmful by themselves

• Granule contents released

• Mediators act on surrounding

• The high-affinity IgE receptor, FcεRI

• Responsible for most allergy symptoms

• Mast cells and basophils constitutively

• The low-affinity IgE receptor, FcεRII

• The high-affinity IgE receptor, FcεRI

• Linking receptors trigger Lyn-mediated

• Triggers PKC and MAPK pathways,

• The low-affinity IgE receptor, FcεRII

• Coclustering with inhibitory receptors

• Inhibition of downstream signaling molecules

• Signaling through FcεR1 activates E3 ubiquitin c-Cbl

• Formed by decarboxylation of histidine amino acid

• Binds to one of four possible histamine receptors (H1-H4)

• Leukotrienes and prostaglandins

• Secondary mediators — formed when membrane phospholipids are

• Active at nanomole levels (1000× more effective than histamine at

• Mast cells and basophils release several of these signaling molecules

• IL-5 recruits and activates eosinophils

• TNF-α may contribute to shock in systemic anaphylaxis

• CXCL-8 (= IL-8) acts as a chemotactic factor, attracting other cells

• GM-CSF stimulates production and activation of myeloid cells, e.g.,

• Early responses occur within minutes of allergen exposure

• Late responses, hours later, a result of recruited cells

• A third phase has been described involving basophils and fibroblasts

• Epinephrine is the immediate treatment

• Localized hypersensitivity reactions

• Pathology is limited to a specific tissue or organ

• Includes allergic rhinitis (hay fever), allergic conjunctivitis, asthma, atopic

• Symptoms result from release of mediators in immediate exposure area

• There are several categories of type I hypersensitivity

• Food allergies: a common type of atopy on the rise

• Can cause vomiting and diarrhea due to smooth muscle contraction

Disorder Symptoms Common triggers Notes about mechanism

Disorder Symptoms Common triggers Notes about mechanism

• Environmental factors include air pollution through to diet, and genetics

• The hygiene hypothesis has been advanced to explain increases in

• Proposes that exposure to some pathogens early in life provides a better T-

• Food allergy initial sensitization takes place through the skin

• Circulating IgE Ab carried in blood to intestinal tissue

• Mediators released that cause symptoms of food allergies

• Skin testing is commonly used

• May also assess and quantify total

• Antihistamines, leukotriene antagonists, and inhalation corticosteroids

• Antihistamines bind and block H1 receptors on target cells

• Leukotriene antagonists work in a manner similar to antihistamines

• Inhalation corticosteroids inhibit innate immune cell activity in airways, treating

• Transfusion reactions are an example of type II

• Involve Ab-mediated destruction of cells by non-IgE Ab

• Blood group Ag are carbohydrates