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Platelets
come first
Fibroblast
migrate in
48 hrs
Macrophage
A
Proliferative
5-7 days – up to 3 months
1.4 Genetics
Inflammatory
6-8 hrs – 3-4 days
Scab
Blood clot forms, and leukocytes
clean wound
Remodelling
3-4 weeks – up to 1 year
Keratinocytes
migrate in
Fibroblasts
proliferating
Subcutaneous fat
Fibroblasts proliferate
and deposit collagen
and ECM
B
Fig. 1.7 Three phases of cutaneous wound healing. (A) Inammatory phase: platelets help form clot, neutrophils and macrophages clean the wound; macrophages
secrete growth factors to stimulate broblasts. (B) Proliferation phase: granulation tissue forms, Re-epithelialization begins, wound contracts. (C) Remodeling: scar
matrix formation. ECM, Extracellular matrix. (Modied from Ramazan E. Advances in fabric structures for wound care. In: Rajendran S. Advanced Textiles for Wound
Care, 2nd ed. Philadelphia: Elsevier; 2019.)
Blood vessels regrow, and granulation
Myofibroblasts provide
maximum wound
contracture at 1-2 weeks
tissue forms
regression of granulation tissue (endothelial cells
are rst to undergo apoptosis and macrophages are
last); collagen remodeling
• Scar strength (High-yield!)
■
1 week: up to 5%
■
3 weeks: 20%
■
3 months: 50%
■
1 year: 80%
Re-generated
epidermis
Re-generated
dermis
(scar tissue)
C
Connective tissue fibrosis occurs
• RNA (ribonucleic acid): molecule composed of nucleic
acids, regulating protein synthesis. Many types of RNAs,
some are noted below:
■
RNAs involved in protein synthesis
Messenger RNA (mRNA): acts as template for
translation of genetic code into protein. RNA
polymerase transcribes DNA at a locus into a singlestranded mRNA
Transfer RNA (tRNA): facilitates translation by acting
as an adaptor molecule to bring correct amino acid
1.4 GENETICS
to matching nucleotide triplet (codon) on the mRNA
Ribosomal RNA (rRNA): acts as a ribozyme within
Basic cell biology of genome
• DNA (deoxyribonucleic acid): molecule composed of
nucleic acids, encoding heritable information. Composed
of a sense and antisense strand.
■
Intron: non-coding nucleotide sequence on DNA (and its
corresponding RNA) that is not translated and is typically
removed prior to translation via splicing. Introns of
varying size and number are found intervening between
exons of a gene (Introns intervene).
■
Exon: coding nucleotide sequence on DNA (and its
corresponding RNA) that will be translated into nal
peptide (Exons are expressed).
ribosomes to catalyze the peptide bond between
amino acids
■
Regulatory RNAs
Short interfering RNA (siRNA)—short, doublestranded RNA (21–23 nucleotides long) that acts to
downregulate gene expression via the RNA
interference (RNAi) pathway in a process known as
“gene silencing.” In this pathway, siRNAs, along with
the RNA-induced silencing complex (RISC), target
specic complementary mRNAs for degradation
MicroRNA (miRNA) – similar to siRNAs, miRNAs
are short RNA sequences (19-25 nucleotides) that
downregulate gene expression via RISC. The major
15
CHAPTER 1 • Basic Science
differences are that that miRNA binds imperfectly to
targets (thus is less specic than siRNA in its targets)
and that miRNA inhibits mRNA translation.
RNA Aptamer- single-stranded RNA that folds into
complex 3-dimensional structure that is able to bind
to target protein with strong afnity
■
RNA therapies
With the wide range of RNA functions, the therapeutic
potential of RNAs is wide. Below, three broad strategies
are briey described.
Encoding proteins – mRNAs are used therapeutically
to instruct host cells to produce proteins of interest.
This strategy is being explored/utilized to produce
protein replacement therapy, to produce cancer
vaccines, and to produce infectious disease vaccines
such as the Moderna and Pzer Covid-19 vaccines.
Regulating nucleic acids – siRNAs or miRNAs are
used to direct the cells RNAi pathway to prevent
translation of harmful mRNA, as may be seen in
depositional disorders (eg amyoid).
RNAs that target proteins – RNA Aptamers bind to
target proteins with strong afnity, typically
inhibiting protein function by occluding key sites
on the protein, such as seen with inhibition of
VEGF in macular degeneration (Pegaptinib)
Inheritance patterns
• Genetic basis of diseases can be straightforward, a single-
gene defect (epidermolysis bullosa), polygenic, or only
partially genetic (diabetes and psoriasis). Examination of
family tree and its affected individuals can help predict
the risk of future offspring to be affected.
• Mendelian inheritance is based upon straightforward,
single-gene inheritance that follows the laws of
segregation and independent assortment (Table 1.9)
• Modifying factors and non-Mendelian inheritance
■
Incomplete or reduced penetrance: not all individuals
with disease genotype will manifest the disease.
Penetrance is an all-or-nothing phenomenon
(complete or incomplete). Incomplete penetrance leads
to the phenomenon whereby the disease is observed to
“skip a generation.” The degree of penetrance refers to
the probability of an individual with the disease
genotype to manifest the disease (in contrast to
variable expression)
Penetrance can be age-related. Examples include
androgenetic alopecia (increased degree of
penetrance later in life), and Hailey-Hailey disease
and Darier’s disease (complete penetrance after a
certain age)
■
Variable expression: variation in severity of the
symptoms of disease that manifest
Darier’s disease and NF1 have variable expression
(broad range of severity)
Genetic anticipation: a type of variable expression in
which severity increases and age of onset of
symptoms is earlier with each successive generation.
Classic example is Huntington’s disease.
■
Mosaicism: due to alteration of DNA during embryonic
development (post-zygotic mutation)
In skin, mosaic expression follows lines of Blaschko
If mutation affects gametes (germline mosaicism),
then mutation may be inherited by offspring.
Example: Mosaic KRT1 or KRT10 mutation → nevi
with epidermolytic hyperkeratosis. If offspring
inherits this mutation, offspring may manifest full
expression of KRT1 or KRT10 mutation →
epidermolytic ichthyosis.
■
Loss of heterozygosity: occurs when presence of single
WT allele maintains normal function of gene, and
subsequently a single mutation (“single hit”) on the
Table 1.9 Mendelian Patterns of Inheritance
Pattern Parents Affected Gender Affected Transmission Recurrence Risk Risk Factors
Autosomal recessive No (carriers),
Autosomal dominant Yes
X-linked recessive Mother a “carrier”aMales have the “complete”
X-linked dominant Yes
a
Unless the proband has a de novo mutation and is therefore the rst generation affected.
b
Does not represent a “pure” X-linked recessive disorder if there are manifestations in female “carriers.”
From DeStefano GM, Christiano AM. Basic principles of genetics. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia: Elsevier;
2018:844–858.
unless parent
carries two
mutated copies
(affected)
a
a
Both equally Disease seen in siblings
Both equally Disease seen in
disease
Female “carriers” may have
mild manifestations (e.g., in
a mosaic pattern)
Predominantly females if lethal
in males during embryonic
development; otherwise
milder in females (often with
a mosaic pattern of skin
lesions) and more severe in
males
b
of proband, not in parents or offspring
Usually only in one gen-
eration
successive generations
No male-to-male
transmission (but
all daughters of an
affected male are
“carriers”)
Affected males have:
(1) no affected sons;
and (2) all daughters
affected
No male-to-male trans-
mission
1 in 4 Consanguinity,
1 in 2 De novo mutations
1 in 2 male children born
to a female “carrier” will
be affected (and 1 in 2
of her female children
will be carriers)
1 in 2 children born to
affected female; may
spontaneously abort
male fetuses if “malelethal” condition
isolated
population (e.g.,
geographically,
linguistically)
De novo mutations
De novo mutations
16
1.5 Ultraviolet Light
WT allele causes a complete loss of function gene.
Important in context of certain tumor suppressor genes
(TSGs), where individuals heterozygous for the TSG are
more susceptible to forming tumors. Examples: Gorlin
syndrome, hereditary leiomyomatosis.
■
Mitochondrial inheritance: both males and females
may be affected, but only passed to offspring via
maternal lineage.
1.5 ULTRAVIOLET LIGHT
Ultraviolet light (Fig. 1.8)
• Ultraviolet light (UV) is made up of:
■
Vacuum UVC (10–200 nm)
■
UVC (200–280 nm)
■
UVB (280–320 nm)
■
UVA (320–400 nm) → divided into UVAII (320–
340 nm) and UVAI (340–400 nm)
• Solar radiation is made up of approximately 50% visible
light, 40% infrared, and 9% UVR
■
UVA is present consistently from sunrise to sunset,
whereas UVB peaks midday
■
UVB is 1000 times more erythemogenic than UVA
UVB signature mutation 5 C → T at pyrimidine
dimer sites (also may see CC → TT)
UVA contributes to mutations via reactive oxygen
species (ROS)
■
Whereas UVA . UVB contributes to immediate
pigment darkening (redistribution of existing melanin),
primarily UVB leads to erythema, burning, delayed
melanogenesis (i.e., tanning) and thickening of the
stratum corneum
■
Depth of UV penetration varies by wavelength; UVA
(longer wavelength) penetrates deeper into dermis
than UVB (shorter wavelength) (Fig. 1.9)
• Light has properties of both waves and photons
• For light to have a cutaneous effect, it must be absorbed
by a chromophore of the epidermis (nucleic acid, protein,
urocanic acid, and melanin) or dermis (hemoglobin and
porphyrins)
• Absorption spectrum: the portion of the electromagnetic
(EM) spectrum that is absorbed by a particular molecule
or chromophore
• Action spectrum: the portion of the EM spectrum that
produces a particular effect
• Vitamin D: UVB converts provitamin D3
(7-dehydrocholesterol) to previtamin D3
■
Previtamin D3 is isomerized in the peripheral
circulation to vitamin D3
■
Vitamin D3 is converted to 25-hydroxyvitamin D3 in
the liver (this is what we measure to assess vitamin D
stores)
■
25(OH) D3 is converted to its active form
1,25-hydroxyvitamin D3 in the kidneys
■
90% of vitamin D produced in this manner, 10% from
dietary intake
Minimal erythema dose
• Minimal erythema dose (MED) is the minimal amount of
a particular UVR that leads to erythema of the exposed
skin 16 to 24 hours after exposure
• MEDs are important to determine the appropriate starting
dose of phototherapy
• Sun protection factor (SPF) measures the degree of
protection an agent confers against UV-induced
erythema
Important denitions
• Irradiance/power (watts) is the intensity of UVR to which
a patient is exposed
• Exposure time (seconds) is the length of time a patient
undergoes UVR treatment
• The dose (J/cm
exposed to
■
These three values are important for the formula: dose
(J/cm
400 nm 320 nm
2
) is the amount of light energy a patient is
2
) 5 irradiance (J/s.cm2) 3 exposure time (s)
Solar radiation
UVA UVB UVC
280 nm 100 nm
Atmosphere/Ozone
Epidermis
Vacuum
UV
200
UVC UVB UVA
200(nm)
Filtered by
the ozone layer
Fig. 1.8 Electromagnetic spectrum. UV, Ultraviolet. (From Hönigsmann H. Skin
diseases in Europe. Photodermatology. Eur J Dermatol. 2009;19(6):658–662.)
290
Visible
400
320(nm)
340 400
Wavelength in
nanometers (nm)
InfraredUltraviolet
400320
UVA 1UVA 2
Dermis
Hypodermis
Fig. 1.9 Ultraviolet (UV) penetration into the layers of the skin. (From PérezSánchez A, Barrajón-Catalán E, Herranz-López M, Micol V. Nutraceuticals for
skin care: a comprehensive review of human clinical studies. Nutrients
2018;10(4):403. This gure was created using Servier Medical Art [https://smart.
servier.com/], licensed under the Creative Commons Attribution 3.0 Unported
License [www.creativecommons.org/licenses/by/3.0/].)
17
CHAPTER 1 • Basic Science
1.6 IMMUNOLOGY
1.6.1 Innate versus adaptive immunity
(Table 1.10)
Innate immunity
• Provides initial defense against epithelial breach and
infectious threats, but with no memory response; recognizes
foreign antigens only (does not recognize self-antigens)
■
Responses may be heightened by repeat microbial
encounters (trained immunity), but does not possess
capacity for true immunologic antigen-specic memory
• Relies on pattern recognition receptors, such as toll-like
receptors (TLRs) and NOD-like receptors (NLRs), that
are expressed by many cell types and recognize conserved
structures among microorganisms, that is, pathogenassociated molecular patterns (PAMPS) or damageassociated molecular patterns (DAMPS)
• Central cellular players: phagocytes, DCs, natural killer
(NK) cells, mast cells, eosinophils, basophils, and innate
lymphoid cells (ILCs)
• Key acellular components include the complement system
and antimicrobial peptides (Cathelicidins, defensins, etc)
Adaptive immunity
• Lag phase before activation, maturation and proliferation of
lymphocytes (B and T cells) in response to specic antigens
• Key lymphocyte subsets include CD4
T cells, gamma-delta T cells, NK T cells and B cells
• Primary response to a new antigen leads to gene
rearrangement of T-cell and B-cell receptors which
optimize the ability to bind and recognize that antigen
upon future exposure
• Secondary response is quicker and larger due to presence
of these “memory” lymphocyte populations that facilitate
a robust antigen-specic response
• The T-cell and B-cell receptors have the potential to
recognize both foreign and self-antigens
■
Normally this potential for self-reactivity is actively
regulated; failure of this regulation leads to
autoimmune disease (often dened by presence of
many self-reactive antibodies)
1
T cells, CD8
1
1.6.2 Immunologic Mediators
Cytokines
• Cytokines bind to cellular receptors → activate or inhibit
downstream signaling pathways → modulate
proliferation, function, and/or differentiation of target
cells (Table 1.11)
• Signaling downstream of several cytokine receptors (e.g.,
IFNa, IFNg, IL-4, IL-6, IL-22, IL-12/23, IL-31) relies on
the JAK-STAT signaling pathway. Genetic associations
with STAT pathway mutations have been reported in
atopic dermatitis, psoriasis, and lupus. Thus, JAKinhibitors such as tofacitinib and ruxolitinib have
therapeutic potential in treatment of various
inammatory skin diseases
■
Write: Tyrosine kinase 2 (TYK2) pairs with JAK1 or
JAK2 to mediate cytokine pathways; deucravacitinib is
an oral TYK2 inhibitor used for psoriasis
• A specic subset of cytokines called chemokines mediate
recruitment/migration of immune cells in tissues. These
will be further discussed later in this chapter
Pattern recognition receptors
• Toll-Like Receptors (TLRs; Table 1.12): recognize
conserved molecules expressed by microbes (PAMPs) or
damaged cells (DAMPs)
■
TLRs are expressed by immune cells as well as
keratinocytes; APCs express the greatest number and
widest variety
■
Some TLRs are expressed on the cell surface and others
intracellularly in endosomes
■
Binding of TLRs by their ligand results in increased
expression of type-1 interferons (to promote antiviral
defense) and activation of NFB which stimulates the
adaptive immune response via expression of cytokines,
chemokines, endothelial adhesion molecules, and costimulatory molecules
■
All TLRs except TLR3 use the Myd88 signaling
pathway following activation; TLR3 signals through
the adaptor protein TRIF; TLR4 can signal through
either pathway
■
IRF5 functions downstream of Myd88 to promote type
1 interferon production in response to endosomal
Table 1.10 Features of Innate and Adaptive Immunity
Innate Adaptive
Characteristics
Specificity For molecules shared by groups of related microbes and molecules
produced by damaged cells
Diversity Limited; recognition molecules encoded by inherited (germline) genes Very large; receptor genes are formed by somatic
Memory None or limited Yes
Nonreactivity to self Yes Yes
Components
Cellular and chemical barriers Skin, mucosal epithelia; antimicrobial peptides Lymphocytes in epithelia; antibodies secreted at
Blood proteins Complement, various lectins and agglutins Antibodies
Cells Phagocytes (macrophages, neutrophils), dendritic cells, natural killer
cells, mast cells, innates lymphoid cells
For microbial and non-microbial antigens
recombination of gene segments in lymphocytes
epithelial surfaces
Lymphocytes
18
1.6 Immunology
Table 1.11 Major Cytokines
Cytokine Immune System Source Principal Effects
IL-1a, IL-1b
IL-2 T cells Proliferation of T, B, and NK cells; T-cell differentiation into memory and effector
IL-4
IL-5
IL-6 T cells, macrophages, endothelial cells Stimulates acute phase protein synthesis, B-cell antibody production and Th17
IL-8 Monocytes, T cells, keratinocytes
IL-10 Tregs, macrophages
IL-12 Macrophages, dendritic cells
IL-13 Th2 cells, group 2 ILCs, mast cells, NKT cells
IL-15 Macrophages
IL-17A/ IL-17F Th17 cells, group 3 ILCs Increased cytokine and chemokine production by keratinocytes and macrophages
IL-18 Monocytes, macrophages, dendritic cells,
IL-22
IL-23 Dendritic cells, macrophages
IL-31 T cells (especially Th2), innate cells, keratinocytes Key role in pruritus; receptor IL-31RA signals through JAK/STAT pathway
IL-36 Keratinocytes Activates keratinocytes and dendritic cells; promotes Th1/Th17; increased in pustular
TGFb
TNF-a
IFN-a/b
IFN-g
GM-CSF T cells, macrophages Maturation of granulocytes and monocytes, activation of macrophages
TSLP Keratinocytes, mast cells, some myeloid cells Th2 differentiation, activation of dendritic cells, eosinophils and mast cells
DIRA, Deciency of interleukin-1 receptor antagonist; GM-CSF, granulocyte colony-stimulating factor; IFN, interferon; IL, interleukin; ILCs, innate lymphoid cells;
MHC, major histocompatibility complex; NK cells, natural killer cells; SNP, single nucleotide polymorphisms; TGF, transforming growth factor; TNF, tumor necro-
sis factor; TSLP, thymic stromal lymphopoietin.
Modied from Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2018.
Macrophages, keratinocytes Increased production of acute phase proteins, fever, lymphocyte activation (Th17
CD41 T cells (Th2, Tfh), mast cells
CD41 T cells (Th2), group 2 ILCs
keratinocytes, fibroblasts
CD41 cells (may co-produce IL-17)
T cells (especially Tregs), macrophages Promotes fibroblast collagen synthesis, inhibits T- and B- cell proliferation and effector
Macrophages, mast cells, NK cells, T cells, and
others
Plasmacytoid dendritic cells (both), macrophages
(a), fibroblasts (b)
T cells (Th1, CD8), NK cells MHC class I and II induction on various cell types, macrophage activation and
differentiation), macrophage activation, ↑ leukocyte/endothelial adhesion; levels
increased in autoinflammatory diseases such as DIRA; signaling inhibited by IL-1
receptor antagonist, of which anakinra is a modified form
cells; at high doses, promotes NK and effector T cells (rationale for use as melanoma
adjuvant therapy); at low doses promotes Treg function
Isotype switching to IgE upon stimulation of B cells; ↑ Th2 proliferation and
differentiation, alterative activation of macrophages; SNPs in IL-4, IL-5, IL-13, and
IL-31 (among others) associated with atopic dermatitis; dupilumab blocks IL4Ra
(shared receptor with IL-13)
Eosinophil activator, B-cell activation, ↑ IgA secretion
differentiation
Chemokine → neutrophil chemotaxis
Inhibition of macrophages/dendritic cells; ↓ expression of IL-12/Th1 response , co-
stimulatory molecules, and class II MHC
Facilitates Th1 differentiation; ↑ IFN-g production and enhanced cytotoxic activity of
NK cells; composed of p40 and p35 subunits (Note: IL-23 also has p40 subunit, but
it is paired with p19; ustekinumab targets shared p40 subunit, while tildrakizumab-
asmn specifically targets IL-23 via p19)
B cells isotype switching to IgE; alternate activation of macrophages: SNPs in IL4R a,
IL5Ra, and IL13Ra confer AD risk
NK-cell differentiation; survival of memory CD81T cells
→ key role in psoriasis pathogenesis and anti-fungal defense; secukinumab and
ixekizumab are monoclonal antibodies to IL-17A
Promotes IFN-g production by T cells and NK cells, neutrophil activation, and monocyte
production of GM-CSF, TNF and IL-1b
Promotes keratinocyte proliferation and hyperplasia, promotes AMP production
Promotes Th17 proliferation and differentiation → key role in psoriasis; composed
of p40 and p19 subunits (Note: IL-12 also has p40 subunit, but it is paired with p35;
ustekinumab targets shared p40 subunit, while tildrakizumab-asmn specifically
targets IL-23 via p19)
SNPs in IL23R, IL-23A and IL-12B (shared subunit of IL-12/IL-23) associated with
psoriasis
psoriasis (spesolimab in an IL-36 receptor antibody used in pustular psoriasis)
and psoriatic arthritis
functions, inhibits macrophage activation
Activation of macrophages and T and B lymphocytes, ↑ proinflammatory cytokine
production, leukocyte/endothelial cell adhesion, cachexia, pyrexia, induction of acute
phase proteins, ↑ MHC class I production
Activation of antiviral/antitumor state (antiproliferative), ↑ MHC class I expression, NK-cell
activation
cytokine synthesis, Th1 differentiation
SNPs associated with atopic dermatitis
TLRs; activating SNPs in IRF5 are a/w systemic lupus
erythematosus (SLE)
• NOD-like receptors (NLRs): a family of more than 20
cytosolic proteins, many of which recognize PAMPs/DAMPs;
well-known NLRs include NOD1 (SNP mutations increase
psoriasis risk) and NOD2 (mutated in Blau syndrome),
both of which lead to NFkB activation, and NLRP3 (aka
cryopyrin/CIAS; mutated in cryopyrin-associated periodic
syndrome); mutations in NLRP1 (a/w vitiligo)
• Note that mutations which augment NFB and related
signaling are a/w psoriasis (i.e., REL, TNIP1, TNFAIP3,
NFKBIA, CARD14, TRAF31P3), whereas those which
diminish NFB signaling, (i.e., hypomorphic alleles of
CARD11) are a/w atopic dermatitis
19
CHAPTER 1 • Basic Science
Table 1.12 Toll-Like Receptors
Receptor Ligand/Key Facts
TLR1 Bacterial lipopeptides (especially gram-negative and
TLR2 Bacterial lipopeptides, lipoteichoic acid on gram-positive
a
TLR3
TLR4 Bacterial lipopolysaccharide (LPS)
TLR5 Bacterial flagellin
TLR6 Bacterial lipopeptides
a
TLR7
a
TLR8
a
TLR9
a
Denotes endosomal localization.
Modied from Male D, Peebles RS Jr, Male V. Mechanisms of innate immunity. In: Immunology. 9th ed. Philadelphia: Elsevier; 2021:46–53.
mycobacterial)
bacteria; peptidoglycan (activated by Propionibacterium
acnes); can dimerize with TLR1 and TLR6.
Viral dsRNA
Viral ssRNA/synthetic ligand imiquimod activates IFN-g
production
Viral ssRNA
Unmethylated CpG DNA (bacterial)
Antimicrobial proteins (AMPs)
• AMPs are produced by keratinocytes, sebocytes, sweat
glands, and innate immune cells in skin
• They contribute to host defense via direct killing of
microbes (collectively they target both gram-positive and
gram-negative bacteria. fungi, viruses, and protozoa)
• Cathelicidins (LL37) and b-defensins are the two most
abundant families of AMPs in skin (others include S100
proteins and RNAses)
• These small cationic peptides are produced constitutively
by keratinocytes
• Their main mechanism of microbial killing is non-
enzymatic membrane disruption
• LL37 binding of host DNA also activates TLR9, which
leads to production of IFNa/b and Th17 activation,
thereby further augmenting host defense
• TLR2 and 1,25-OH vitamin D3 are both important in
regulating the production of skin AMPs
• LL37 and b-defensins are expressed at relatively low levels
in healthy skin but signicantly upregulated in psoriasis
and rosacea; by comparison, upregulation of AMPs is
partially suppressed in atopic dermatitis
The complement system
• Consists of small proteins found freely in blood or on cell
membranes, which are usually present in an inactive state
as zymogens
• Most complement proteins are synthesized in the liver
and also are acute phase reactants
• Upon activation, they acquire protease activity that
facilitates cleavage or activation of subsequent protein(s) in
the complement cascade, thereby amplifying the response
• Stable activation is only achieved after attachment to
microbes, antibodies, or dying cells
• Normal host cells possess proteins that inhibit
complement activation
■
Thus, full functioning of the complement system is
usually restricted to the cell surface of microbes or sites
where antibodies are bound to antigens
• Complement has a number of important functions
■
Direct lysis of bacteria
■
Opsonization of bacteria (complement binds to an
organism and augments phagocytosis)
■
Chemotaxis of innate immune cells
■
Clearing of immune complexes (hence, complement
deciency syndromes are a/w increased risk of lupus)
■
Activating immune responses
■
Anaphylaxis
• Three complement pathways:
■
Classical pathway: activated by antibodies (IgM and
IgG, except IgG4) bound to antigen
■
Alternative pathway: activated by microbial cell
surface structures without antibodies
■
Lectin pathway: activated by mannose-binding lectin
which attaches to carbohydrates on the surface of
microbes
• Although they differ in early activation events, all three
pathways converge on the central event of C3 cleavage by
C3 convertase and generation of the biologically active
molecule C3b
• Likewise, following cleavage of C5, all three pathways are
identical in the nal steps which assemble C5b to C9 into
the membrane attack complex (MAC), which creates
transmembrane pore in cell surfaces to facilitate lysis/
death (Fig. 1.10)
• Key molecules involved in the three complement
pathways as well as those that regulate their activity are
listed in Table 1.13
1.6.3 Cells of signicance
B Cells
• B cells are formed from pluripotent progenitor stem cells
in the bone marrow
• Located in the lymphoid follicle of lymph node
• Main function is antibody/immunoglobulin production
and differentiation into plasma cells (requires surface
immunoglobulin receptors to bind antigen)
• B-cells isotype switch (can switch from one antibody
class to another) if they interact with T-helper cells
(IgM to IgG, IGA, or IgE); isotype is determined by the
heavy chain
• B cells can also present antigen on major
histocompatibility complex (MHC) class II to CD4
(following recognition and binding of the antigen to B-cell
receptor and subsequent endocytosis)
• Initial exposure to antigen leads to a primary immune
response:
■
Has lower antibody production (typically IgM with a
lower-afnity antibody)
■
Some B cells differentiate into memory B cells or
plasma cells
• Subsequent exposure leads to a secondary immune
response:
■
Memory B cells more rapidly develop into plasma cells
■
↑ High-afnity antibody production (IgA, IgE, and
IgG)
■
↑ Isotype switching in the presence of T-helper cells,
CD40 ligand, and other cytokines
1
T cells
20
1.6 Immunology
Fig. 1.10 Complement activation pathways. The classical
complement cascade is activated by antibody bound to
microbial surfaces, which is a binding site for the C1 complex. The alternative pathway is activated by the binding of
spontaneously generated C3b to microbial surfaces. Microbial bound C3b binds factor B, which is converted to
factor Bb, forming C3 convertase. The lectin pathway is
activated by the binding of mannose-binding lectin (MBL)
to mannose residues on microbial surfaces. MBL binds
MBL-associated serine proteases (MASP), which bind and
cleave C4 and C2, forming C3 convertase. (From McDonald DR, Levy O. Innate immunity. In: Rich RR, Fleisher TA,
Shearer WT, Schroeder HW Jr, Frew AJ, Weyand CM, eds.
Clinical Immunology: Principles and Practice. 5th ed.
Philadelphia: Elsevier; 2019.)
• B cell markers/receptors: FC receptor, MHC class II,
various complement receptors, CD19, CD20 (target of
rituximab), CD79a
• BCL2 is an anti-apoptotic molecule which provides a survival
advantage for malignant B cells; BCL6 is a transcription
factor that generally represses pathways within B cells to help
regulate the germinal center response; both are used as
immunohistochemical markers of healthy germinal center B
cells as well as certain types of B-cell lymphomas
• Antibody structure has two identical heavy and two
identical light chains with variable and constant domains
that are connected by disulde bonds. The variable
region (Fab) has a unique/specic antigen-binding
domain. The constant region (Fc) interacts with cell
surface Fc receptors on various immune cells (e.g.,
phagocytes, NK cells, mast cells) → binding of Fc by Fc
receptors promotes phagocytosis of Ig-coated particles and
cellular activation or degranulation (e.g., FcRI binding of
IgE on mast cells) (Fig. 1.11, Table 1.14). Of note, papain
cleaves antibody into two Fab fragments and one Fc
fragment
T cells (majority of lymphocytes)
• Derived from the bone marrow, but mature in the
thymus; reside in paracortex of lymph nodes
• T cells are divided into CD4
Th2, Th17, Tfh, and Treg) and CD8
minor populations include gd T cells and NK T cells
(Table 1.15)
1
• CD4
T cells recognize extracellular antigens presented by
a professional APC on MHC class II
1
• CD8
T cells recognize intracellular antigens presented by
any nucleated cell on MHC class I
• Activation of naïve T cells requires both recognition of
antigen (signal 1) and co-stimulation (signal 2) → this
leads to proliferation and differentiation that is further
1
T-helper cells (Th1,
1
cytotoxic T cells;
inuenced via specic cytokines provided by the APC or
other cells
• Signal 1: T-cell receptor recognizes its cognate antigen
complexed with MHC class I/II molecules on a
professional or non-professional APC (see 1.6.4 Major
Histocompatibility Complex)
• Signal 2: For successful activation of T cells, co-
stimulation via a secondary receptor is required; in the
absence of this, T cells become anergic; signal 2 can
alternatively be inhibitory, shutting down activation of the
T cell (Fig. 1.12)
■
CD28 on T cell binds to CD80 (B7-1) or CD86 (B7-2)
on APCs → stimulation
■
CD2 on T cells binds to LFA-3 on APCs → stimulation
■
LFA-1 on T cells binds to ICAM-1 on APCs →
stimulation
■
CD40L on T cell binds to CD40 on APCs or phagocytes
→ stimulation
■
CTLA-4 on T cell (often a Treg) binds to B7-1 and B7-2
on APCs → inhibition
■
PD-1 on T cell binds to PDL-1 on APCs (or tumor
cells) → inhibition
■
Clinical relevance: blocking these inhibitory pathways
is the rationale behind cancer immunotherapies that
enable greater T-cell activation and antitumor activity
in melanoma and other malignancies, for example,
pembrolizumab and nivolumab block PD-1,
ipilimumab blocks the CTLA-4 (Fig. 1.13)
• IL-2 is produced after T-cell activation and leads to
proliferation of antigen-specic T cells; Tregs can provide
a sink for IL-2 via the high-afnity receptor CD25 to limit
effector cell activation
• PTPN22 is a tyrosine kinase involved downstream of TCR
activation; mutations in PTPN22 are a/w autoimmune
skin diseases such as lupus and vitiligo
• Clonal expansion of the responding T cells during the
primary response is followed by contraction of this
21
CHAPTER 1 • Basic Science
Table 1.13 Important Players in the Complement System
Name Pathway Key Function(s)
C1 Classical Initiates classical pathway activation
C1q Classical
C1r Classical Serine protease, cleaves and activates C1s
C1s Classical
C2 Classical/Lectin C2b (formerly referred to as C2a) is serine protease that contributes enzymatic activity to C3 and
C3 All Cleaved by C3 convertase into C3a and C3b
C3a All C3a is an anaphylatoxin stimulating inflammation
C3b All C3b is an opsonin. It binds to microbial pathogens facilitating phagocytosis.
C3 convertase All Cleaves C3 into C3a and C3b
C4 Classical/Lectin C4 b binds to surface of microbe or cells where antibody is bound or complement is activated
C5 All C5b initiates assembly of MAC
C5 convertase All
C5b-C9 All Components of membrane attack complex (MAC); defects associated with infection by
Mannose-binding lectin (MBL),
ficolins
MASP1-3 Lectin Homology to C1r/C1s in classical pathway; form complex with lectins, collectins or ficolins; serial
C1 esterase inhibitor (C1 inh) Regulatory role in
Factor B Alternative Cleaved by factor D, producing Ba and Bb. Bb is the active subunit, a serine protease, that joins
Factor D Alternative Cleaves factor B
C4-binding protein, factor I, factor
H, membrane cofactor protein,
decay-accelerating factor
Data from Abbas AK, Lichtman AH, Pillai S. Effector mechanisms of humoral immunity. In: Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier;
2018:275–298.
Lectin Agglutinin, opsonin, complement fixing. MBL activates the lectin pathway: binds to cell surface
classical pathway
Regulatory role Limit activity of key molecules above (especially C3b and C4b) by displacement (which
Binds to Fc portion of antibody (IgM or IgG [IgG3 . IgG1 . IgG2; IgG4 does NOT activate clas-
sical complement pathway]) that has bound antigen; can also bind apoptotic cells and cationic
surfaces.
Deciency most strongly associated with lupus
Serine protease, cleaves C4 and C2 → C3 convertase (C4b/C2b)
C5 convertases
Most common deciency; association with SLE of early onset with more extensive skin involve-
ment but mild systemic disease course
C3a is an anaphylatoxin stimulating inammation
C3b is an opsonin. It binds to pathogens → phagocytosis
It is also a component of C3 convertase (in alternative pathway, C3 convertase is stabi-
lized by properidin; X-linked deciency in properidin confers susceptibility to fulminant meningococcal disease)
In all pathways, it is part of C5 convertase
In classical/lectin pathways: composed of C4b/C2b
In alternative pathway: composed of C3b and Bb
C4b binds C2 for cleavage by C1s
C4a is an anaphylatoxin stimulating inammation
Defect in C4A/B both associated with lupus
C5a is an anaphylatoxin stimulating inammation
Assembly of C3b 1 C4b2b. Cleaves C5 into C5a and C5b.
encapsulated organisms (Neisseria, pneumococcus)
polysaccharides (via pattern recognition) on microbes → cleavage of C2 and C4.
activation eventually leads to cleavage of C4
Binds to C1r and C1s to dissociate them from C1q; defects associated with hereditary
angioedema
C3b to form C3 convertase
disassembles convertase complexes) or cleavage. For example, factor H inhibits formation of C3
convertase.
population and indenite persistence of memory T cells;
these cells:
■
Respond more rapidly to antigen stimulation than
naïve cells
■
Memory T cells in the skin consist of both recirculating
memory T cells (Ccr71, L-selectin
resident memory T cells (CCR7
1/–
CD103
• Activation of a specic CD4
)
1
1/–
) and tissue-
neg
, L-selectin
neg
, CD691,
helper response often has
the effect of suppressing another, that is, Th1 suppresses
Th2/Th17, Th17 suppresses Th2 (mutations in STAT3
lead to hyperactivation of Th2 in Job/Hyper IgE
syndrome)
22
1
• CD4
and CD81 T cells play a critical role in cell-mediated
immunity, which provides defense against intracellular
threats (invasive bacteria, viruses, cancer), in contrast to
humoral immunity, in which antibodies help ght
extracellular threats. Both CD41 Th1 and CD81 T cells help
to activate phagocytes via IFNg production and CD40L.
CD81 T cells, that is, cytotoxic T lymphocytes, kill infected/
cancerous cells.
• Leukocyte extravasation through vascular endothelium:
■
Selectins bind carbohydrates to facilitate rst step of
leukocyte “rolling” (i.e., P and E selectin expressed on
the endothelium bind to CLA glycoprotein on immune
cells; mutations in GDP fucose transport, needed to
Secreted IgG Membrane IgM
1.6 Immunology
Heavy
chain
N
N
Light
chain
Fc receptor/
complement
binding sites
C C
Antigenbinding site
Hinge
C
CH1
H
N
V
H
N
V
L
C
L
N
N
C C
Fab
2
region
Fc
region
CH3
Tail piece
C
C
Disulfide bond
Ig domain
A B
Fig. 1.11 Structure of an antibody molecule. (A) Schematic diagram of a secreted IgG molecule. The antigen-binding sites are formed by the juxtaposition of V
and VH domains. The heavy chain C regions end in tail pieces. The locations of complement- and Fc receptor-binding sites within the heavy chain constant
regions are approximations. (B) Schematic diagram of a membrane-bound IgM molecule on the surface of a B lymphocyte. The IgM molecule has one more C-
domain than IgG has, and the membrane form of the antibody has C-terminal transmembrane and cytoplasmic portions that anchor the molecule in the plasma
membrane. (From Abbas A, Lichtman AH, Pillai S. Antibodies and antigens. In: Cellular and Molecular Immunology . 9th ed. Philadelphia: Elsevier; 2018. Courtesy of
Dr. Alex McPherson, University of California, Irvine.)
Antigenbinding site
V
H
CH1
C
L
CH2
CH3
C
4
H
Plasma
membrane
of B cells
CC
N
N
V
L
L
Table 1.14 Classes of Immunoglobulins
Isotype IgM IgD IgG IgE IgA
Structure Pentamer Monomer Monomer Monomer Monomer, dimer
Complement
activation
Bacterial toxin
neutralization
Antiviral activity No No Yes No Yes
Binding to mast cells
and basophils
Additional properties First antibody in
Modied from Actor JK. Elsevier’s Integrated Review: Immunology and Microbiology. 2nd ed. Philadelphia: Elsevier; 2012.
express ligands for these selectins on neutrophils, lead
to type 2 leukocyte adhesion deciency)
■
Integrins covalently bind various ligands to promote
attachment between cells or to ECM; their ligand
afnity is increased by chemokines and antigen
recognition (LFA-1 on T cells binds to ICAM-1 on
Strong No Yes, except IgG4 No Weak
Yes No Yes No Yes
No No No
B-cell antigen receptor Antibody-dependent
primary immune
response; Naïve
B cell antigen
receptor
cell cytotoxicity;
opsonization for
phagocytosis;
Feedback inhibition
of B cell activation;
Only antibody
that crosses the
placenta
Yes (→ release of
mediators)
Mast cell
degranulation
(immediate
hypersensitivity),
eosinophilmediated helminthic
responses
No
Active as dimer on
epithelial/mucosal
surfaces
activated endothelium to promote next step in
extravasation; mutations in subunit of LFA lead to type 1
leukocyte adhesion deciency)
■
Chemokines are a subfamily of cytokines that facilitate
leukocyte movement from blood and within tissues
(Table 1.16).
23
CHAPTER 1 • Basic Science
Table 1.15 Key T Lymphocyte Subsets
Lymphocyte Type
(Defining Transcription
Factor, if Applicable)
CD41 Th1 (Tbet, STAT1,
STAT4)
CD41 Th2 (GATA3,
STAT6)
CD41 Th17 (RORgT/
STAT3)
CD41 Tfh (Bcl6)
CD41 Treg (FOXP3)
CD81 CTL
g/d T cell
NK T cells
IFN, interferon; IL, interleukin; CTCL, cutaneous T cell lymphoma; AMPs, antimicrobial peptides; SNPs, single nucleotide polymorphisms; AA, alopecia areata;
MHC, major histocompatibility complex; TNF, tumor necrosis factor; UV, ultraviolet; IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked
Data from Abbas AK, Lichtman AH, Pillai S. Differentiation and functions of CD4 1 effector T cells. In: Cellular and Molecular Immunology . 9th ed. Philadelphia:
Elsevier; 2018:225–242.
Key Cytokines
and/or Effector
Molecules
IFN-g, and IL-12
stimulate Th1
differentiation;
Th1 cells produce
IL-2, IFN-g
(downregulates
Th2 pathway), IL12 and TNF-a
IL4 stimulates Th2
proliferation by
activating STAT6
and GATA 3; Th2
cells produce IL-4,
IL-5, IL-6, IL-10
(suppresses Th1
response), IL-13
IL-16, IL-17, IL-22,
IL-23, IL-36,
TNF-a
IL-21 B cells Antibody production Extracellular
IL-10, CD25,
CTLA4
Granzyme, perforin,
Fas ligand, IFN-g;
TNFa
IL-17 Neutrophils Suppress Th1 system via
IFN-g, IL-4
Principal Target
Cells Major Immune Effect
Macrophages Macrophage activation and
Eosinophils, mast
cells
Neutrophils Neutrophil recruitment and
Effector
lymphocytes
and innate
immune cells
Infected cells,
opsonized
cells (recognize
intracellular
antigens
presented on
MHC class I)
phagocytosis; IgG2 and
IgG3 class switching →
complement activation
Activation of eosinophils via
IL-5 and (indirectly) of mast
cells via IgE cross-linking;
alternative macrophage
activation; IgE and IgG4
class switching in B cells
activation; increase AMPs,
barrier function
Suppress Th1 system via
IL-10
Killing (cytotoxicity) via perforin
(perforates cell) & granzyme
(enters cytoplasm) →
apoptosis. Can also kill cells
via Fas ligand, which binds
to Fas on target cell.
IL-10
Recognize lipid antigens
presented by CD1 molecules;
provide B cell help
Microbial Target/
Role in Host
Defense Role in Disease
Intracellular
pathogens
Helminths Important in normal
Extracellular
bacteria and fungi
pathogens
Limiting tissue
damage by other
cell types
Intracellular
pathogens,
cancer
Extracellular
bacteria and fungi
Myocobacteria and
other lipid-rich
pathogens
Cell-mediated immunity,
autoimmunity; chronic
inflammation (i.e.,
tuberculoid leprosy,
cutaneous leishmaniasis,
sarcoidosis, delayed-
type hypersensitivity;
CTCL, psoriasis)
humoral immunity
Excessive response
in allergy (i.e.,
atopic dermatitis,
lepromatous leprosy,
Sézary, disseminated
leishmaniasis)
Autoimmunity; inflammation
(i.e., psoriasis, allergic
contact dermatitis)
Autoimmunity
(autoantibodies)
Mutations in Foxp3 lead
to autoimmunity (IPEX
syndrome); SNPs related
to Treg function associated
with vitiligo and AA
Autoimmunity; inflammation
(vitiligo; checkpoint
blockade therapy); CD8
lymphomas are highly
aggressive
Enriched in leprosy and
cutaneous leishmaniasis;
lymphomas of g/d types
are highly aggressive
May contribute
to UV-induced
immunosuppresion
Chemokines implicated in atopic dermatitis:
CCL5/CCL11 (Eos/Th2), CCL17, CCL18, CCL22,
CCL26; in certain settings (e.g., chronic lesions,
Asian cohorts) CCL20 (Th17), and CXCL9/10 (Th1)
Chemokines implicated in psoriasis: CCL17, CCL20
(Th17), CXCL1/8 (Neuts), CXCL9/10 (Th1),
CX3CL1 (Th1)
Chemokines implicated in vitiligo: CCL5, CXCL8,
CXCL9/10 (Th1/CD8)
Chemokines implicated in alopecia areata: CXCL1
(Neuts), CXCL9/10 (Th1/CD8)
Innate lymphoid cells
• Bone marrow–derived cells share similar morphology to
lymphocytes but lack T-cell receptors; thought to
function mainly through cytokine secretion
24
• Three major subsets: ILC1, ILC2, ILC3 (somewhat
analogous to Th1, Th2, and Th17 subsets)
■
ILC1: express Tbet transcription factor; secrete IFNg;
contribute to viral defense
■
ILC2: express GATA3 transcription factor; secrete IL-5,
IL-13; defend against helminths, contribute to allergic
inammation
■
ILC3: express RORgt transcription factor; secrete IL-17,
IL-22; may be increased in psoriasis
NK cells
• Key component of the innate immune system
• Like ILCs, they share lymphocyte morphology and
originate from a common bone marrow precursor but
lack T-cell receptors
• Cell surface markers include CD2, CD56, and CD16