BASIC IMMUNOLOGY 1 : AUTOIMMUNE

DISEASES

Prapaporn Pisitkun, M.D.

Associate Professor
Division of Allergy, Immunology and Rheumatology
Department of Medicine
Ramathibodi Hospital
Mahidol University
 Outlines
How the How the
The basic Autoimmunity,
immune immune
of immune autoinflammatory,
system system
system and COVID-19
works regulates
Distinguish the Innate/Adaptive
Innate immunity Autoimmunity
pathogens interaction

Adaptive Response to APC/T cells

Autoinflammatory
immunity antigens interaction
Regulatory and COVID-19
Create memory
inhibitory associated
response
function inflammation
 Outlines
How the How the
The basic Autoimmunity,
immune immune
of immune autoinflammatory,
system system
system and COVID-19
works regulates
Distinguish the Innate/Adaptive
Innate immunity Autoimmunity
pathogens interaction

Adaptive Response to APC/T cells

Autoinflammatory
immunity antigens interaction
Regulatory and COVID-19
Create memory
inhibitory associated
response
function inflammation
 INNATE AND ADAPTIVE IMMUNITY

• Defense microbes
• Early reactions
• Specific for
structures of related
microbes

Cellular and Molecular Immunology 8th edition

 FEATURES OF INNATE AND ADAPTIVE IMMUNITY
Innate Adaptive
Characteristics
Specificity Molecules shared by For microbial and non-
microbes microbial Ag
Diversity Limited; germline encoded Very large; receptors are
produced by SHM
Memory None Yes
Non-reactivity to self Yes Yes
Components
Cellular and chemical Skin, epithelia, anti- Lymphocytes in epithelia;
barriers microbial peptide, Ab secreted by epithelia
microbiota, enzyme surfaces
Blood proteins Complement, other Antibodies
Cells Macrophages, neutrophils, Lymphocytes
NK cells, dendritic cells
IMMUNOLOGICAL CELLS OF INNATE AND ADAPTIVE IMMUNITY
 MATURATION OF MONONUCLEAR PHAGOCYTES

 Phagocytes
 Neutrophils and
macrophages, are cells
whose primary function is to
ingest and destroy microbes
and get rid of damaged
tissues
 Critical for defense against
both extracellular and
intracellular bacteria as well
as fungal pathogens

Cellular and Molecular Immunology 8th edition

FUNCTIONS OF MACROPHAGES

Macrophages are
activated by
microbial products
such as LPS and
by NK cell–derived
IFN-γ.

Cellular and Molecular Immunology 8th edition

 MATURATION OF DENDRITIC CELLS

o Dendritic cells
o Antigen-presenting
cells (APCs)
capture microbial
and other antigens,
display them to
lymphocytes, and
provide signals
that stimulate the
proliferation and
differentiation of
the lymphocytes
o Cytokine
producers

Cellular and Molecular Immunology 8th edition

FUNCTIONS OF NK CELLS

o The effector functions of

NK cells are to kill
infected cells

o To aid defense against

viral and intracellular
infections via production
of IFNg, which activates
macrophages to destroy
phagocytosed microbes

Cellular and Molecular Immunology 8th edition

FUNCTIONS OF ACTIVATING AND INHIBITORY RECEPTORS OF NK CELLS
Inhibitory receptor Inhibitory receptor not
enganged enganged

Missing self

Cellular and Molecular Immunology 8th edition

INNATE LYMPHOID CELLS
o Lymphocyte
morphology Bone marrow
o Fully capable of
performing effector
functions (shared by T
cells) without the need
for clonal expansion
and differentiation

o The ability to produce

various cytokines, but
they do not rearrange
antigen receptor genes
and do not express
TCRs

Cellular and Molecular Immunology 8th edition

NEUTROPHIL EXTRACELLULAR TRAPS (NETS) FORMATION
PATHWAYS
 COMPONENTS OF INNATE IMMUNE SYSTEM

 Biologically active substances

 Type I IFNs and IFN-induced proteins: Critical role in defense against viral infection
 Cytokines
 The acute phase response and complement
 Secreted by hepatocytes in response to inflammatory cytokines IL-1 and IL-6
 Inflammasomes
 NLRP-inflammasome responses are induced by a wide variety of cytoplasmic stimuli
(infections, cell stress, including microbial products, environmentally or endogenously
derived crystals, and reduction in cytosolic potassium ion (K+) concentrations)
CYTOKINES OF INNATE IMMUNITY (1)
Cytokine Principal Cell Source Principal Cellular Targets and Biologic Effects
Tumor necrosis Macrophages, T cells Endothelial cells: activation (inflammation,
factor coagulation)
(TNF) Neutrophils: activation
Hypothalamus: fever
Muscle, fat: catabolism (cachexia)
Interleukin-1 Macrophages, endothelial Endothelial cells: activation (inflammation,
(IL-1) cells, some epithelial cells coagulation)
Hypothalamus: fever
Liver: synthesis of acute-phase proteins
T cells: TH17 differentiation
Interleukin-12 Macrophages, dendritic cells T cells: TH1 differentiation
(IL-12) NK cells and T cells: IFN-γ synthesis, increased
cytotoxic activity
Type I IFN-α: macrophages, All cells: antiviral state, increased class I MHC
interferons plasmacytoid expression
(IFN-α, dendritic cells NK cells: activation
IFN-β) IFN-β: fibroblasts
CYTOKINES OF INNATE IMMUNITY (2)

Cytokine Principal Cell Source Principal Cellular Targets and Biologic Effects
Interleukin-10 Macrophages, T cells (mainly Macrophages, dendritic cells: inhibition of IL-12
(IL-10) regulatory T cells) production and expression of costimulators and
class II MHC molecules
Interleukin-6 Macrophages, endothelial Liver: synthesis of acute-phase proteins
(IL-6) cells, T cells B cells: proliferation of antibody-producing cells
T cells: TH17 differentiation
Interleukin-15 Macrophages, others NK cells: proliferation
(IL-15) T cells: proliferation (memory CD8+ cells)
Interleukin-18 Macrophages NK cells and T cells: IFN-γ synthesis
(IL-18)
Interleukin-23 Macrophages and dendritic T cells: maintenance of IL-17–producing T cells
(IL-23) cells
Interleukin-27 Macrophages and dendritic T cells: TH1 differentiation; inhibition of TH17 cells
(IL-27) cells NK cells: IFN-γ synthesis
BIOLOGIC ACTIONS OF TYPE I INTERFERONS

Cellular and Molecular Immunology, 8th edition

EFFECTS OF TYPE I INTERFERON-ACTIVATED GENE
EXPRESSION IN DIFFERENT CELLS

Immune activation in
Genetically susceptible individual

Non-hematopoietic cells
Monocytes MHC
Differentiation into DC Type I interferon Chemokine expression

Interferon signature
400 interferon-stimulated genes

Dendritic cells Natural killer cells

MHC, BAFF MHC
Costimulatory molecules Killing capacity
T-cell activating capacity Interferon

T cells B cells
MHC activation MHC
B-cell activating capapcity Immunoglobulin class switch
Plasma-cell differentiation
 COMPLEMENT : BIOSYNTHESIS

 Majority of plasma complement components are synthesized in the liver

 Exceptions are C1q (intestinal epithelium) and factor D (adipose tissue).
 C7 are synthesized in the liver (<60%) and bone marrow-derived cells (granulocytes)

 Extrahepatic complement production

 Astrocytes or other glial cells (behind blood-brain barrier)
 Local complement production plays role in transplantation, promote allograft rejection

 Common transcriptional inducer of complement genes is IFN-ℽ, IL-1, and IL-6

 C1 binding to Binding of a C3b binding to
COMPLEMENT ACTIVATION antigen-antibody plasma lectin activating surfaces
complexes to microbes (microbial cell walls)

Classical Lectin Alternative

 Complement activation C4
Antibody Antibody
 Stimulation of inflammatory reactions dependent independent

 Opsonization of pathogens
C3
 Complement-Mediated Cytolysis Activation of C3 and
Generation of C5 convertase

Activation of C5

Lytic attack
pathway
FUNCTIONS OF COMPLEMENT
THE EARLY STEPS OF
COMPLEMENT
ACTIVATION BY THE
ALTERNATIVE,
CLASSICAL, AND
LECTIN PATHWAYS
LATE STEPS OF COMPLEMENT ACTIVATION AND FORMATION OF
THE MEMBRANE ATTACK COMPLEX (MAC)
RECEPTORS FOR FRAGMENTS OF C3

Receptor Ligands Cell Distribution Function

Type 1 complement C3b > C4b > iC3b Mononuclear phagocytes, Phagocytosis, clearance of
receptor (CR1, CD35) neutrophils, B and T immune complexes,
cells, erythrocytes, promotes dissociation of C3
eosinophils, FDCs convertases by acting as
cofactor for cleavage of
C3b, C4b
Type 2 complement C3d, C3dg > iC3b B lymphocytes, FDCs, Co-receptor for B cell
receptor (CR2, CD21) nasopharyngeal activation, trapping of
epithelium antigens in germinal
centers, receptor for EBV
Type 3 complement iC3b, ICAM-1; also Mononuclear phagocytes, Phagocytosis, leukocyte
receptor (CR3, Mac-1, binds microbes neutrophils, NK cells adhesion to endothelium
CD11b/CD18) (via ICAM-1)
Type 4 complement iC3b Mononuclear phagocytes, Phagocytosis, cell
receptor (CR4, p150,95, neutrophils, NK cells adhesion?
CD11c/CD18)
 Inflammasome

o A multiprotein complex in the cytosol

of mononuclear phagocytes, dendritic cells,
and other cell types that proteolytically
generates the active form of IL-1β from the
inactive pro-IL-1β precursor

o The formation of the inflammasome

complex, which includes NLRP3 (a NOD-like
pattern recognition receptor) and caspase-1,
is stimulated by a variety
of microbial products, cell damage–
associated molecules, and crystals

Cellular and Molecular Immunology; 8th edition

Nat. Rev. Immunol., 2019
ADAPTIVE IMMUNITY (SPECIFIC OR ACQUIRED IMMUNITY)

Humoral

Active Passive

• Contact with • Antibodies pass through

the disease placenta or mother’s milk
• Vaccine • IVIG

Cellular
 T helper cells
 T regulatory
 Th1
 Th2
 Th17
 T cytotoxic cells
ACTIVE AND PASSIVE IMMUNITY
B CELL MATURATION

Cellular and Molecular Immunology; 8th edition

T CELL MATURATION

Cellular and Molecular Immunology; 8th edition

 Outlines
How the How the
The basic Autoimmunity,
immune immune
of immune autoinflammatory,
system system
system and COVID-19
works regulates
Distinguish the Innate/Adaptive
Innate immunity Autoimmunity
pathogens interaction

Adaptive Response to APC/T cells

Autoinflammatory
immunity antigens interaction
Regulatory and COVID-19
Create memory
inhibitory associated
response
function inflammation
INNATE IMMUNE RECOGNITION
RECOGNITION OF MICROBES
 Recognizes molecular structures
that are produced by microbial
pathogens
 Pathogen-associated molecular
patterns (PAMPs): represent
targets of innate immune
recognition
 PAMPs are unique to
microorganisms, they are not
unique to pathogens
RECOGNITION OF DAMAGED SELF
 Recognizes endogenous molecules
that are produced by or released from
damaged and dying cells
 Damage-associated molecular
patterns (DAMPs)
 DAMPs could be a result of cell
damage caused by infections, or
indicate sterile injury to cells caused
by any of myriad reasons (chemical
toxins, burns, trauma, or ischemia)
EXAMPLES OF PAMPS AND DAMPS
Pathogen-Associated Molecular Patterns Microbe Type
Nucleic acids ssRNA Virus
dsRNA Virus
CpG Virus, bacteria
Proteins Pilin Bacteria
Flagellin Bacteria
Cell wall lipids LPS Gram-negative bacteria
Lipoteichoic acid Gram-positive bacteria
Carbohydrates Mannan Fungi, bacteria
Glucans Fungi

Damage-Associated Molecular Patterns

Stress-induced proteins HSPs
Crystals Monosodium urate
Nuclear proteins HMGB1
 PATTERN
RECOGNITION
MOLECULES OF
THE INNATE
IMMUNE
SYSTEM
TOLL-LIKE RECEPTORS
Recognition of
Cytoplasmic RNA
Virus
by RLRs
Recognition of
Cytoplasmic
DNA and IFN
Production
Innate DNA sensing induces the activation of signaling pathways
to stimulate type I IFN expression

Barrat, Elkon and Fitzgerald.

Ann. Rev. Med. 2016.
Inflammasome

NLRP3
INFLAMMASOME
PRIMING AND
ACTIVATION

Nat. Rev. Immunol., 2019

CREATE MEMORY RESPONSE
 Stimulation of adaptive
immunity by innate
immune responses
 Antigen recognition by
lymphocytes provides
signal 1 for the activation
of the lymphocytes
 Molecules induced on
Cytokines
host cells during innate
immune responses to
microbes provide signal 2

Antigen-specific T and B
lymphocytes
CHECKPOINTS IN LYMPHOCYTE MATURATION

Cellular and Molecular Immunology; 8th edition

PHASES OF HUMORAL IMMUNE RESPONSE

Cellular and Molecular Immunology; 8th edition

PHASES OF T CELL RESPONSES

Cellular and Molecular Immunology; 8th edition

CYTOKINES PRODUCED DURING INNATE IMMUNE
RESPONSES PROMOTES ADAPTIVE IMMUNE RESPONSES

 IL-12 stimulates the differentiation of naive CD4+ T cells to the TH1

subset of effector cells

 IL-1, IL-6, and IL-23 stimulate the differentiation of naive CD4+ T cells
to the TH17 subset of effector cells

 IL-15 promotes the survival of memory CD8+ T cells

 IL-6 promotes the production of antibodies by activated B cells

 Outlines
How the How the
The basic Autoimmunity,
immune immune
of immune autoinflammatory,
system system
system and COVID-19
works regulates
Distinguish the Innate/Adaptive
Innate immunity Autoimmunity
pathogens interaction

Adaptive Response to APC/T cells

Autoinflammatory
immunity antigens interaction
Regulatory and COVID-19
Create memory
inhibitory associated
response
function inflammation
ROLE OF DENDRITIC CELLS IN ANTIGEN CAPTURE AND
PRESENTATION
PROPERTIES OF ANTIGENS RECOGNIZED BY T LYMPHOCYTES

 Most T lymphocytes recognize

only short peptides
 The antigen receptors of CD4+
and CD8+ T cells are specific for
peptide antigens that are
displayed by MHC molecules
 A single T cell can recognize a
specific peptide displayed by only
one of the large number of
different MHC molecules that
exist. This phenomenon is called
MHC restriction
FUNCTIONS OF DIFFERENT ANTIGEN-PRESENTING CELLS
CROSS-PRESENTATION OF ANTIGENS TO CD8+ T CELLS

• All nucleated cells can present peptides, derived from cytosolic protein antigens, to CD8+
CTLs
• Other cell types that express class II MHC molecules and may present antigens to T cells
include endothelial and some epithelial cells
 MAP OF THE HUMAN MHC

MHC molecules are

required to present antigens
to T lymphocytes, the
expression of these proteins
in a cell determines whether
foreign (e.g., microbial)
antigens in that cell will be
recognized by T cells.
EXPRESSION OF MHC MOLECULES

• The expression of MHC

molecules is increased by
cytokines produced during
both innate and adaptive
immune responses

• Enhancement of class II
MHC expression by IFN-γ
PATHWAYS OF ANTIGEN PROCESSING AND PRESENTATION
LIGAND-RECEPTOR PAIRS INVOLVED IN T CELL ACTIVATION
ROLE OF CD40 IN T CELL ACTIVATION

Cellular and Molecular Immunology; 8th edition

 MECHANISMS OF
HELPER T CELL-MEDIATED
B CELL ACTIVATION

Cellular and Molecular Immunology; 8th edition

THE GERMINAL CENTER REACTION IN A LYMPH NODE
IG HEAVY CHAIN ISOTYPE SWITCHING
 PROPERTIES OF TH1, TH2 AND TH17 SUBSETS OF
CD4+ HELPER T CELLS

Cytokines

Cellular and Molecular Immunology; 8th edition

FUNCTIONS OF COSTIMULATORS IN T CELL ACTIVATION
 THE MAJOR MEMBERS
OF THE B7 AND CD28
FAMILIES

The outcome of T cell

activation is influenced by a
balance between engagement
of activating and inhibitory
receptors of the CD28 family
INHIBITORY SIGNALING IN
LYMPHOCYTES

Ligand binding results in

phosphorylation of the ITIM
tyrosine by a Src family kinase,
followed by
recruitment of an SH2 domain–
containing tyrosine
phosphatase that can attenuate
immune receptor signaling
REGULATION OF B CELL ACTIVATION BY FCGR2B

Cellular and Molecular Immunology; 8th edition

MECHANISMS THAT LIMIT INNATE IMMUNE
RESPONSES
 IL-10 is a cytokine that is produced by and inhibits activation of
macrophages and dendritic cells
 IL-10 inhibits the production of various inflammatory cytokines by activated
macrophages and dendritic cells, including IL-1, TNF, and IL-12
 Mononuclear phagocytes produce a natural antagonist of IL-1 (IL-1
receptor antagonist or IL-1RA) that is structurally homologous to the
cytokine and binds to the same receptors but is biologically
inactive
 Negative signaling pathways block the activating signals generated
by pattern recognition receptors and inflammatory cytokines
THE MECHANISM OF THERAPEUTIC COSTIMULATORY BLOCKADE

A fusion protein of the

extracellular portion of CTLA-
4 and the Fc tail of an IgG
molecule is used to bind to
and block B7 molecules,
thus preventing their
interaction with the activating
receptor CD28 and inhibiting
T cell activation
 Outlines
How the How the
The basic Autoimmunity,
immune immune
of immune autoinflammatory,
system system
system and COVID-19
works regulates
Distinguish the Innate/Adaptive
Innate immunity Autoimmunity
pathogens interaction

Adaptive Response to APC/T cells

Autoinflammatory
immunity antigens interaction
Regulatory and COVID-19
Create memory
inhibitory associated
response
function inflammation
AUTOIMMUNE DISEASES

 Autoimmunity: reactions against self antigens. Failure of the normal

mechanisms of self-tolerance results in reactions against one’s own
cells and tissues

 The diseases caused by autoimmunity are referred to as

autoimmune diseases
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): THE PROTOTYPIC
IMMUNE COMPLEX–MEDIATED DISEASE

THE CURRENT MODEL OF PATHOGENESIS OF SLE

Nature reviews Rheumatology (2016)

INDUCTION OF AUTOIMMUNITY

 Inherited susceptibility
 The strongest associations have been found within MHC locus
 Non-MHC susceptibility genes in GWAS study
 Pathways of B-cell and T-cell activation or innate receptor signaling

 Action of environmental triggers via genetically polymorphic

pathways

 Chronic inflammation is a process that takes over from acute

inflammation if the infection is not eliminated or the tissue injury is
prolonged
 Balance of autoimmunity

Tolerogenic antigen signals Immunogenic antigen signals

chronic, early acute, late

Immunogenic costimuli
Tolerogenic costimuli LPS, TNF-
FasL/Fas CD3d/CD21
TGF-β, IL-10 B7/CD28
CTLA4, FcgR2B CD40L/CD40
CD5, CD22 IL-7, IL-15, IL-17
Microbial DNA/RNA (TLR)

INHIBITORY SIGNALS ACTIVATING SIGNALS

TOLERANCE IMMUNITY

Adapted from C.C.Goodnow,

Genetic/Epigenetic Lancet 2001; 357
 POSTULATED
MECHANISMS
OF AUTOIMMUNITY

Innate immunity

Adaptive immunity

Innate & adaptive

immunity
Cellular and Molecular Immunology; 8th edition
CENTRAL AND PERIPHERAL TOLERANCE TO SELF ANTIGENS
CENTRAL T CELL TOLERANCE

During their maturation in

the thymus, many
immature T cells that
recognize antigens with
high avidity are deleted,
and some of the surviving
cells in the CD4+ lineage
develop into regulatory T
cells
THE FUNCTION OF AIRE IN DELETION OF T CELLS IN THE THYMUS
MECHANISMS OF PERIPHERAL T CELL TOLERANCE
MECHANISMS OF T CELL ANERGY
MECHANISMS OF ACTION OF CTLA-4
REGULATORY T CELLS

• Production of the
immunosuppressive
cytokines IL-10 and TGF-β
• Reduced ability of APCs to
stimulate T cells
• Consumption of IL-2
 IL-2 MAINTAINS FUNCTIONAL
REGULATORY T CELLS AND THUS
CONTROLS IMMUNE RESPONSES

• IL-2 stimulates the survival,

proliferation, and differentiation of
antigen-activated T cells

• IL-2 is required for the survival and

function of regulatory T cells
CENTRAL TOLERANCE IN B CELLS
PERIPHERAL TOLERANCE IN B CELLS

• B cells that encounter self

antigens in peripheral
tissues become anergic or
die by apoptosis
• In some situations,
recognition of self antigens
may trigger inhibitory
receptors that prevent B cell
activation
ROLE OF INFECTION IN THE DEVELOPMENT OF
AUTOIMMUNITY

Cellular and Molecular Immunology; 8th edition

TYPES OF ANTIBODY-MEDIATED DISEASES
EFFECTOR MECHANISMS
OF ANTIBODY-MEDIATED DISEASE

Disease Antigen involved

SLE DNA, nucleoproteins
PAN HSsAg
Post-strep GN Streptococcal cell wall antigen
Serum sickness Various proteins
MECHANISMS OF T CELL–MEDIATED DISEASES.

Disease Specificity of pathogenic T cell

RA Collagen, Citrullinated protein
MS Myelin basic protein
T1 DM Antigen of pancreatic islet B cells
IBD Enteric bacteria
Psoriasis Skin antigen
NOVEL THERAPIES FOR INFLAMMATORY DISEASES
A MODEL FOR THE
PATHOGENESIS OF
SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
 TRIGGERS OF IFN PRODUCTION

 SLE sera (immune complex) can induce IFN production by peripheral

blood mononuclear cells (PBMC) of healthy donors
 Autoantibodies associated with IFN production in SLE include anti-
dsDNA, as well as anti-RNA binding proteins (anti-RBP) such as anti-Ro,
and anti-RNP
 Additional causes for excess formation of apoptotic and necrotic cells may
be exposure of keratinocytes to ultraviolet (UV) light, exposure to viral
infection, or IFN itself
 Evidences suggest that type I IFNs are directly involved in
the pathogenesis of SLE

(1) IFN immunotherapy can induce

lupus
(2) Increased IFN-regulated gene
expression in 50% of adults with
SLE (and up to 100% of children
SLE)
(3) Polymorphisms in IFN pathway
genes have been implicated in the
pathogenesis of lupus in genome
wide association studies

Nat. Rev. Rheumatol., 2010

RESPONSE TO INFECTION: NEUTROPHIL
EXTRACELLULAR TRAPS (NETS)

Nature Reviews Immunology 11, 519-531 (August

2011)
MECHANISMS OF NET-MEDIATED PATHOLOGY
Overview of major pathogenetic pathways in SLE
T regulatory cell
Apoptosis
(nuclear)
Self-Ag

Naïve T cell Activated T cell CD40

B cell
CD80/86 CD28
CD40L
TLRs APC T cell help
CD80/86 CTLA-4 Ag presentation
CD40 CD40L Auto-Abs,
Chemokines Cytokines Immune
Interferon
complexes
MØ
Complement
activation
Granulocytes
Cytokines
Cytokines
Degranulation

Inflammation
Tissue damage
A MODEL FOR THE PATHOGENESIS
OF RHEUMATOID ARTHRITIS

• Citrullinated proteins induced by environmental

stimuli elicit T cell and antibody responses in
genetically susceptible individuals

• The T cells and antibodies enter joints, respond to

the self proteins, and cause tissue injury mainly
by cytokine secretion and perhaps also by
antibody-dependent effector mechanisms
 TYPE I INTERFERONOPATHIES
 A novel set of inborn errors of
immunity
 Inappropriate and/or excessive IFN
output resulting from
1. Inappropriate stimulation of the type I
IFN response pathway, or
2. Defective negative regulation of the
type I IFN system.
 Aicardi–Goutieres syndrome
(AGS)
 Spondyloenchondrodysplasia
(SPENCD)
 Systemic lupus erythematosus
(SLE)
 Complement deficiency
 Stimulator of interferon genes-
associated vasculopathy with
onset in infancy (SAVI)
STING–INTERFERON PATHWAY

N Engl J Med 2014; 371:568-571

DOI: 10.1056/NEJMe1407246
STIMULATOR OF INTERFERON GENES (STING)–ASSOCIATED
VASCULOPATHY WITH ONSET IN INFANCY (SAVI)

 Clinical Features

 Telangiectatic lesions on the nose and cheeks

 Violaceous, scaling, atrophic plaques on the
hands
 Dense neutrophilic infiltrate with karyorrhexis
throughout the vessel wall
 Interstitial lung disease

N Engl J Med 2014; 371:507-518

AUTOINFLAMMATORY SYNDROMES

 Dysregulated activation of the inflammasome due to autosomal gain-of-

function mutations in one or another of its component proteins leads to
inappropriately triggered and excess IL-1 production
 The result is recurrent attacks of fever and localized inflammation, most
commonly in joints and intestines
 Spontaneous inflammation without an overt inciting trigger
LOCAL AND SYSTEMIC ACTIONS OF CYTOKINES IN INFLAMMATION
INFLAMMASOME ACTIVATION IN
AUTOIMMUNE DISEASES

C.-A. Yang, B.-L. Chiang / Journal of Autoimmunity (2015)

IL-1-MEDIATED DISEASES

 Familial Mediterranean Fever (FMF)

 Cryopyrin Associated Periodic Syndromes (CAPS)

 TNF receptor associated periodic syndrome (TRAPS)

 Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS) /

Mevalonate Kinase deficiency
 The Monogenic Autoinflammatory Bone Diseases (DIRA, Majeed
syndrome)
 Blau syndrome / early onset sarcoidosis (pediatric granulomatous
arthritis, PGA)
 MICROBIOTA AND AUTOIMMUNITY

 Commensal organisms in the intestines are required for and regulate

innate immune responses in the gut, and adaptive immune responses

 Provision of ligands for adaptive immunity

 Cross-reactivity with self-antigens

 Influencing the Cells of the Immune System

 Germ-free mice
 Decreased numbers of T and B cells, levels of IgA and IgG antibodies, and a strong
skewing toward the Th2 CD4+ T cells
 Introduction of microbes to germ-free mice restores the Th1 and Th17 compartments
 The gut microbiota impinges on non-gut autoimmunity

Mechanisms of gut
microbiota regulation of
human epigenome and
immune responses.

Journal of Autoimmunity. (2017)

GUT AND LUNG AXIS
 Microbiomes of the gut and lungs maintain
bidirectional crosstalk.
 Bacterial ligands (lipopolysaccharides; LPS)
and bacterial metabolites (short-chain fatty
acids; SCFAs) from the gut enter the
bloodstream and travel to the lung where
they modulate immune responses and lung
microbial composition.
 Gut intestinal epithelial cells interact with the
microbiome to stimulate immune responses.
 The airway microbiota maintains lung
homeostasis by acting on resident immune
cells and regulating cytokine levels.
 Bothimmune cells and cytokines may enter
the bloodstream and subsequently affect the
gut microbiome.

https://doi.org/10.1016/B978-0-12-819265-8.00048-6
 COVID-19 ASSOCIATED
HYPER-INFLAMMATORY SYNDROME
IMMUNE RESPONSE TO COVID-19 INFECTION

Hyperresponsiveness Hypercoagulability Organ failure

of immune system Journal of Autoimmunity,(2020)
CHRONOLOGY OF EVENTS DURING SARS-COV-2 INFECTION

Nature Reviews Immunology, (2020)

SAR-COV2 IMMUNE RESPONSE

ADE = antibody dependent enhancement Nature Reviews Immunology (2020)

Immune response to SARS‐CoV‐2 and mechanisms of
immunopathological changes in COVID‐19

Allergy, 2020
 IMMUNE RESPONSE TO SARS-COV-2

EFFECTIVE RECOVERY SEVERE SARS-COV-2 INFECTION

Production of Interferons Low interferon
Activation of NK-Mediated Killing of Infected Cells Insufficient recruitment of virus-specific T Cells
Activation of Dendritic Cells, Macrophages, and Delay viral clearance
Neutrophils
Recruitment and Activation of Virus Specific CD4 T Virus induced tissue damage and inflammation
Cells
Activation of CD8 Mediated Cytotoxicity and B Cell Virus induced lymphocyte apoptosis
Production of Antibodies Inflammation and cell death induced cytokine storm
Block of Viral Spreading Cytokine storm induced macrophage activation
syndrome and multi-organ failure
Anti-Inflammatory Recovery

Vaccines, (2020)
 DEVELOPMENTAL DIFFERENCES IN PEDIATRIC AND ADULT
IMMUNE RESPONSE TO VIRAL INFECTION

Innate cell function reaches adult levels in early childhood. B cell and T cell function
continues to develop throughout childhood. By contrast, regulatory T cell function wanes
with aging.
Nat Immunol. 2022 Feb;23(2):177-185.
COMPARISON OF IMMUNE ALTERATIONS BETWEEN
PEDIATRIC AND ADULT COVID-19

Rheumatology International (2021) 41:19–32

Factors that reduce the severity of
SARS-CoV-2 infection in children

- Reduced expression of ACE2

- More robust IFN response
- More T cells owing to greater
thymic output, more T cells that
recognize non-structural viral
proteins
- Less T cell exhaustion

Nat Immunol. 2022 Feb;23(2):177-185.

THE TEMPORAL RELATIONSHIP BETWEEN SARS-COV-2
INFECTION AND DEVELOPMENT OF MIS-C

Nat Rev Rheumatol. 2021 Dec;17(12):731-748.

POSSIBLE MECHANISMS
IMPLICATED IN ABERRANT

ACTIVATION OF IMMUNE

CELLS IN MIS-C

Nat Rev Rheumatol. 2021 Dec;17(12):731-748.

COMPARATIVE INCIDENCE OF CLINICAL SIGNS IN MIS-C AND
KAWASAKI DISEASE
COMPARISON OF THE IMMUNE RESPONSE TO SARS-COV-2
IN CHILDREN AND ADULTS

Nat Immunol. 2022 Feb;23(2):177-185.

FEEDFORWARD LOOP BETWEEN INNATE AND ADAPTIVE
IMMUNE SYSTEMS IN SYSTEMIC AUTOIMMUNITY