Download 1. T cells

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MEMO
Clinical symptoms
resulting from abnormalities of
complements
Various skin diseases, including those with
systemic lupus erythematosus (SLE) like
symptoms, Raynaud’s syndrome, angioneurotic edema and opportunistic infections, may
be caused by congenital abnormalities and
deficiencies of complementary proteins.
B. Immunocompetent cells
a. Immunocompetent cells in general
1. T cells
T cells express T-cell receptors that recognize the antigen
information associated with MHC molecules (Fig. 3.3). T cells
are produced in the bone marrow and develop in the thymus. T
cells are classified by function into CD4 positive helper T cells
(helper T lymphocyte; Th) and CD8 positive cytotoxic T lymphocytes (Tc).
Th contains CD4 on the cell surface, by which Th adheres to
MHC class II. Therefore, Th reacts against antigen-presenting
cells and B cells, which contain MHC class II. Th differentiates
into subtype Th1 or Th2, depending on the surrounding cytokine
environment (Fig. 3.3). Th1 secretes cytokines such as IL-2 and
IFN-g , activating histiocytes (macrophages) primarily, and it
induces cellular immunity by evoking various inflamatory reactions. Th2 secretes IL-4 and IL-5, activates antibody production
in B cells, and inactivates foreign substances (humoral immunity). It is known that Th1 is involved mostly in type IV allergy
while Th2 is involved in type I allergy (atopic diseases).
Tc contains CD8, by which Tc is associated with MHC class I
to initiate cytotoxic immunity (Fig. 3.3); in this way, non-self
cells and virus-infected cells are destroyed. Tc is important in
transplantation immunity, tumor immunity and viral infections.
Recently, the presence of another subtype – regulatory T cell
(Treg) – has been identified. Treg is considered to be involved in
immune control, including suppression of autoimmune disease
onset. It is also known that some Th and Tc circulate in the blood
after an immune reaction to guard against re-infection.
2. B cells
B cells derive from hematopoietic stem cells in the bone marrow, after which they differentiate. They react against foreign
antigens in lymph nodes, the spleen, and peripheral tissues to differentiate into antibody-forming cells (plasma cells); B cells produce antibodies in this process. B cells contain MHC class II and
B. Immunocompetent cells
activate T cells as antigen-presenting cells. Immunoglobulins
expressed on the surface of B cells react to the corresponding targeted antigens to convey information to T cells. When activated,
most of the B cells differentiate into antibody-producing cells
that provide antibodies against the antigens and die in the course
of time – except for some that differentiate into memory B cells
so that they are able to produce antibodies immediately upon reinfection.
3. Histiocytes (macrophages)
Histiocytes (macrophages) are bone marrow-derived cells that
have intense phagocytic reactivity. There are dermal-originated
histiocytes and monocytes circulating in the blood. Histiocytes
degrade phagocytosed antigen proteins into peptides and present
the antigen information to T cells by MHC class II (Fig. 3.3). In
inflammation, histiocytes proliferate, migrate to loci, leave various cytokines, and induce phagocytosis of causative factors and
injure the infected cells. Histiocytes may fuse to form enlarged
cells. They are the main cells to form granulomas in chronic
inflammation (Chapter 2).
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Th1 is involved in cytotoxic immunity,
including apoptosis; Th2 is involved in
humoral immunity, including type I allergy.
Th1 and Th2 release mutually inhibitive
cytokines; it is thought that this maintains a
balance between the two (Th1/Th2 balance).
In recent years, various allergies and malignant tumors have been explained by the concept of Th1/Th2 imbalance. For example,
atopic dermatitis and type I allergy are
thought to be caused by a Th2-dominated
immune reaction, and organ-specific autoimmune diseases and arterial sclerosis are
thought to result from a Th1-governed
immune reaction.
Th1/Th2 balance
4. Mast cells
Mast cells play a central roll in type I allergy. They contain
high-affinity IgE receptors (FceRI) and considerable amounts of
histamines. When binded with IgE and further cross-linked by an
antigen to react to IgE, mast cells are activated to release inflammatory cytokines that lead to dermal edema in erythema or
urticaria. Mastcytosis is caused by tumorous proliferation of mast
cells.
5. Eosinophils
Eosinophils have phagocytic and cytotoxic functions. They are
associated with atopic diseases (type I allergy), autoimmune blistering diseases, and parasitic infections. Eosinophils are activated
by Th2-derived IL-5. Morphologically, they are characterized by
having multiple eosinophilic granules (Fig. 3.5). They do not
usually exist in normal skin.
20 m m
Fig. 3.5 Eosinophil.
The cytoplasm is eosinophilic (stained red in
Hematoxylin-Eosin). Note the multiple nuclei.
6. Neutrophils
Neutrophils are phagocytic and play a large role in fighting
bacterial infections (Fig. 3.6). They are hardly ever found in normal skin. They are also activated in inflammatory diseases. Neutrophilic infiltration (pustule) is observed in psoriasis vulgaris
and Sweet’s disease.
20 m m
Fig. 3.6 Neutrophil.
In skin, cytoplasm of neutrophils is less
eosinophilic than that of eosinophils. A neutrophil has a multiple segmented nuclei.
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Immunology of the Skin
7. Basophils
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Like eosinophils and neutrophils, basophils are also granular
leukocytes, and they contain multiple basophilic granules. They
contain histamines in the granules and have FceRI on the surface.
They are involved in type I allergy. The functions of basophils
are similar to those of mast cells.
b. Immunocompetent cells specific to skin
1. Langerhans cells
Fig. 3.7 Langerhans cell electron micrograph.
Langerhans cells are bone marrow-derived cells and appear as
dendritic cells. They contain the characteristic racquet-shaped
Birbeck granules in the cellular cytoplasm (Figs. 3.7 and 3.8).
Langerhans cells are antigen-presenting cells that are specific to
the skin. Langerhans cells adhere to the epidermal keratinocytes
by E-cadherins, functioning as sentinels against foreign antigens.
When presenting an antigen to T cells, Langerhans cells are
known to detach from the epidermis to reach the regional lymph
nodes through the lymphatic vessels (Fig. 3.9). On the surface of
the human Langerhans cells are MHC class II, CD1a, and S-100
proteins; this is useful for identifying them. With stimulation by
antigens, they express CD80 and CD86 by the functions of GMCSF and TNF-a secreted from keratinocytes to strongly activated
T cells.
Langerhans cells disappear in lesions in graft-versus-host disease (GVHD).
2. Keratinocytes
Fig. 3.8 Birbeck granules (arrows).
High-power magnification of Fig.3.7. Birbeck
granules look like tennis racquets in sectional
image.
Keratinocytes are involved not only in cornification but also in
skin immunity. They produce and secrete various cytokines to
stimulate immuno-incompetent cell activation (Table 3.3). IL-1
a is particularly abundant in keratinocytes. When keratinocytes
are destroyed by inflammation or injury, IL-1a is released to
evoke activation of lymphocytes, histiocytes (macrophages), and
vascular endothelial cells, which induces an inflammatory reaction.
3. Dermal dendrocytes
Dermal dendrocytes are bone marrow-derived cells found in
the upper dermal layers. Since dermal dendrocytes are characterized by expressing the factor XIIIa on their surface and have antigen-presenting ability, dermal dendrocytes are considered to be
Langerhans-related cells in the dermis. They increase in number
in inflammatory diseases and Kaposi sarcoma.
C. Immunity, Allergic reactions
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Table 3.3 Main cytokines secreted by keratinocytes.
Classification, cytokines
Main functions
Multifunctional cytokines
IL-1a
IL-6
IL-7
IL-12
IL-15
IL-18
TNF-a
MIF
Induction of secondary cytokines
6444447444448
Interleukin (IL)
Modulation of adhesion molecules
Modulation of activation and migration of T cells, B
cells and macrophages
Activation of endothelial cells and fibroblasts
Modulation of activation and migration of Langerhans
cells (IL-1a, TNF-a)
Induction of fever and acute inflammatory proteins
Chemotactic factor: associated with leukocyte migration
IL-8
Activation and migration of T cells and neutrophils
Colony stimulating factor: associated with leukocyte proliferation
GM-CSF
Activation of granulocytes, macrophages, T cells and
Langerhans cells
G-CSF
Proliferation of granulocytes
M-CSF
Proliferation of macrophages
Growth factor: associated with local cutaneous reactions
TGF-a
Proliferation of keratinocytes
b-FGF, PDGF
Proliferation of fibroblasts and endothelial cells
Suppression factor: modulates immunity
TGF-b
Suppression of keratinocytes and endothelial cells
IL-10
Suppression of immunity through Th1 cells
IL: interleukin, TNF: tumor necrosis factor, MIF: macrophage migration
inhibitory factor, GM-CSF: granulocyte macrophage colony-stimulating factor, G-CSF: granulocyte colony-stimulating factor, M-CSF: macrophage
colony-stimulating factor, TGF: tumor growth factor, b-FGF: basic fibroblast
growth factor, PDGF: platelet derived growth factor
C. Immunity, Allergic reactions
Skin is a major organ where immune/allergic reactions occur.
Various skin diseases have been increasingly understood by the
concept of immunity and allergic reactions, which are generally
classified into the four categories established by Coombs & Gell
(Table 3.4).
1. Type I allergy
Type I allergy is caused mainly by mast cells. Since a reaction
occurs 5 to 15 minutes after an antigen (allergen) is administered,
it is also called an immediate hypersensitivity. Mast cells with
IgE on the surface react to antigens, and chemical mediators such
as histamines and leukotrienes are then secreted by the mast cells
(Chapter 8). These chemical mediators enhance vascular permeability, to produce edema; in addition, they induce migration of
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