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The Immune System
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The purpose of the Immune System is defense and
protection through a system of surveillance
This surveillance operates on the simple
principal of distinguishing self from non-self
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As long as the system works things are good
But when the system doesnt work, things are bad
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Effectors of the Immune System
Histocompatibility Genes
Immune Mechanisms
Autoimmune Disorders
Immunodeficiency Diseases
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Effectors of the Immune System
Cells and Cytokines
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Effectors Cells of the Immune System
T Lymphocytes B Lymphocytes Macrophages Dend
rtitic Langerhans Cells Natural Killer Cells
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T Lymphocytes
In the blood, T cells constitute 60 to 70 of
peripheral lymphocytes Each T cell is
genetically programmed to recognize a specific
cell-bound antigen by means of an
antigen-specific T-cell receptor (TCR)
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T Lymphocytes
CD3 molecular complex
The CD3 proteins are a group of proteins
associated with the TCR and are used as a
marker or means of identifying T-cells
in-vitro
The CD3 proteins do not bind antigen but are
involved in the transduction of signals into the
T cell after it has bound the antigen
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T Lymphocytes
CD3 molecular complex
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T Lymphocytes
T cells also express a variety of other
molecules, including CD4, CD8, and many so-called
accessory molecules, such as CD2, CD11a, CD28,
and CD43
Of these, CD4 and CD8 are particularly important
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T Lymphocytes
CD4 and CD8
They are expressed on two mutually exclusive
subsets of T cells. CD4 is expressed on
approximately 60 of mature CD3 T cells, whereas
CD8 is expressed on about 30 of T cells. Thus
in normal healthy persons, the CD4-CD8 ratio is
about 21
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T Lymphocytes
The CD4 and CD8 T cells perform distinct but
somewhat overlapping functions
The CD4 T cell can be viewed as helper cells. By
secreting soluble factors (cytokines), CD4 T
cells influence the function of virtually all
other cells of the immune system, including other
T cells, B cells, macrophages, and natural killer
(NK) cells
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T Lymphocytes
The CD8 T cells, in contrast to CD4 T cells,
also secrete cytokines, but tend to be suppressor
cells, and primarily mediate their functions by
acting as cytotoxic cells.
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T Lymphocytes
These molecular complexes, CD3,CD4,CD8, etc. are
important , as they provide the basis for
identification and enumeration of T-cells and
T-cell functional subsets
Thus, they have given rise to a shorthand
nomenclature used to describe T lymphocytes
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T Lymphocytes
T3 Cells T-Lymphocytes CD3, OKT3 OKT11 T4
Cells T-helper cells CD4, OKT4 T8
Cells T-suppressor CD8, OKT8 T-cytotoxic

T3 Cells 60-70 of peripheral lymphocytes T4
Cells 60 of T-Lymphocytes T8 Cells 30 of
T-Lymphocytes T Null Cells 10 of T-Lymphocytes
(CD3,CD4-,CD8-) T4/T8 21
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T Lymphocyte Subpopulations
As with the T8 cells having 2 subpopulations,
suppressor and cytotoxic, the T4 cells also
appear to have 2 subpopulations
T-helper-1 and T-helper-2
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T Lymphocytes
The T-helper-1 (TH1) subset synthesizes and
secretes interleukin-2 (IL-2) and
interferon-gamma (IFN-g), whereas TH2 cells
produce IL-4 and IL-5 This distinction is
significant because the cytokines secreted by
these subsets have different effects on other
immune cells.
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T Lymphocytes
In general, the TH1 subset is involved in
facilitating the macrophage-dependent immune
responses, including induction of delayed
hypersensitivity and production of opsonizing
antibodies. The TH2 subset aids in the synthesis
of other classes of antibodies
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B Lymphocytes
B lymphocytes constitute 10 to 20 of the
circulating peripheral lymphocyte population
On antigenic stimulation, B cells form plasma
cells that secrete immunoglobulins, which in turn
are the mediators of humoral immunity
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B Lymphocytes
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B Lymphocytes
B cells recognize antigen via the B-cell antigen
receptor complex. Immunoglobulin M (IgM),
present on the surface of all B cells,
constitutes the antigen-binding component of the
B cell receptor As with T cells, each B-cell
receptor has a unique antigen specificity
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B Lymphocytes
In addition to membrane IgM, the B-cell antigen
receptor complex contains a transmembrane
proteins Iga and Igb. Like the CD3 proteins of
the TCR, Iga and Igb do not bind antigen but are
essential for signal transduction through the
receptor
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B Lymphocytes
B cells also express several other molecules that
are essential for B cell function. These include
complement receptors (CD21), Fc receptors, and
CD19 and CD20 proteins
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B Lymphocytes
Thus, these CD19 and CD20 proteins also serve as
markers or as a means for identification of B
cells So that B cells are CD18, CD20
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Macrophages
Macrophages play a major role in inflammation,
but also have many activities in the immune
response.
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Macrophages
They are required to process and present antigen
to immunocompetent T cells. Because T cells (in
contrast to B cells) cannot be activated by
soluble antigens, presentation of processed,
membrane-bound antigens by macrophages or other
antigen-presenting cells is required for
induction of cell-mediated immunity.
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Macrophages
They produce a variety of cytokines
Macrophages lyse tumor cells by secreting toxic
metabolites and proteolytic enzymes and, as such,
may play a role in immunosurveillance
Macrophages are important effector cells in
certain forms of cell-mediated immunity, such as
the delayed hypersensitivity reaction
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Dendritic and Langerhans Cells
Dendritic cells are widely distributed. They are
found in lymphoid tissue and in the interstitium
of many nonlymphoid organs, such as the heart and
lungs. Similar cells within the epidermis have
been called Langerhans cells
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Dendritic and Langerhans Cells
Dendritic cells and Langerhans cells are
extremely efficient in antigen presentation.
Although they share antigen-presenting capacity
with macrophages, in contrast to the latter cell
type, they are weakly or not at all phagocytic
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Natural Killer (NK) Cells
Approximately 10 to 15 of the peripheral blood
lymphocytes do not bear TCR or cell-surface
immunoglobulins. In the past, these non-T, non-B
cells were called null cells.
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Natural Killer (NK) Cells
These lymphocytes are have an innate ability to
lyse a variety of tumor cells, virally infected
cells, and some normal cells, without prior
sensitization. NK cells are believed to be a
part of the natural (as opposed to adaptive)
immune system that may be the first line of
defense against neoplastic or virus-infected cells
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Natural Killer (NK) Cells
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Natural Killer (NK) Cells
Two cell-surface molecules, CD16 and CD56, are
used to identify NK cells. Of these, CD16 is of
functional significance. It represents the Fc
receptor for IgG and endows NK cells with another
functionthe ability to lyse IgG-coated target
cells. This phenomenon, is known as
antibody-dependent cytotoxicity (ADCC)
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Natural Killer (NK) Cells
Morphologically, NK cells are somewhat larger
than T and B lymphocytes and, in contrast to
these two cell types, contain azurophilic
cytoplasmic granules.
NK cells are sometimes referred to as large
granular lymphocytes.
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Histocompatibility Genes
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Histocompatibility Molecules
Originally identified as antigens that evoke
rejection of transplanted organs,
histocompatibility molecules are now extremely
important for the induction and regulation of the
immune response and for certain nonimmunologic
functions
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Histocompatibility Molecules
The principal physiologic function of the cell
surface histocompatibility molecules is to bind
peptide fragments of foreign proteins for
presentation to appropriate antigen-specific T
cells
T cells (in contrast to B cells) can recognize
only membrane-bound antigens, and hence
histocompatibility antigens are critical to the
induction of T-cell immunity
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Histocompatibility Molecules
Several genes code for histocompatibility
antigens, but those that code for the most
important transplantation antigens are clustered
on a small segment of chromosome 6.
This cluster constitutes the human major
histocompatibility complex (MHC) and is also
known as the human leukocyte antigen (HLA)
complex because MHC-encoded antigens were
initially detected on the white cells
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Histocompatibility Molecules
MHC gene products are classified into three
categories. Class I and Class II genes encode
cell surface glycoproteins, and Class III genes
encode components of the complement system.
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Histocompatibility Molecules
Class I antigens are expressed on all nucleated
cells and platelets. They are encoded by three
closely linked loci, designated HLA-A, HLA-B, and
HLA-C
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Histocompatibility Molecules
Class II antigens are coded for in a region
called HLA-D, which has three subregions HLA-DP,
HLA-DQ, and HLA-DR
Class II antigen tissue distribution is limited
in that they are found mainly on antigen
presenting cells(monocytes/macrophages),B cells
and some activated T cells
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Histocompatibility Molecules
Class III proteins are coded within the MHC and
are the components of the complement system, C2
and C3
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Histocompatibility Molecules
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Histocompatibility Molecules
The major function of the HLA molecules is to
present antigen to T cells. In this capacity the
HLA molecules play a significant function in
induction of both the humoral and cell mediated
immune system
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Histocompatibility Molecules
In general the Class I molecules are involved
with cell mediated immune reactions while Class
II molecules are involved with humoral immune
mechanisms
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Histocompatibility Molecules
Class I HLA molecules are required for antigen
binding in T8 cell-mediated
cytotoxicimmune reactions
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Histocompatibility Molecules
Class II molecules are required for antigen
presentation to T4 cell in the humoral immune
response
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Histocompatibility Molecules
In part, the presence of these HLA molecules on
human cells is what enables the immune system to
distinguish self from non-self
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Histocompatibility Molecules
The HLA complex is what is responsible for tissue
and organ rejection in transplants
Just as with blood types, tissue types must match
the recipient or the immune system of the
recipient will attack(reject) the foreign
(non-self) transplanted tissue
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Histocompatibility Molecules
HLA and Disease Association
A variety of diseases have been found to be
associated with certain HLA types
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Histocompatibility Molecules
Disease HLA Risk
Ankylosing Spondylitis B27 90x Postgonococcal
arthritis B27 14x Rheumatoid Arthritis DR4
6x Chronic Active hepatitis DR3 14x Type 1
diabetes DR3 5x DR4 7x
DR3/DR4 14x

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Histocompatibility Molecules
The diseases that show association with HLA can
be grouped into 3 categories (1) inflammatory
diseases, including ankylosing spondylitis and
several postinfectious arthropathies, all
associated with HLA-B27 (2) inherited errors of
metabolism, such as hemochromatosis (HLA-A3) and
21-hydroxylase deficiency (HLA-BW47 (3)
autoimmune diseases, including autoimmune
endocrinopathies, associated with alleles at the
DR locus
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Histocompatibility Molecules
The mechanisms underlying these associations are
not well understood
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Cytokines
The induction and regulation of the immune
responses involve multiple interactions among
lymphocytes, monocytes, inflammatory cells
(neutrophils), and endothelial cells.
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Cytokines
Many such interactions depend on cell-to-cell
contact however, many interactions and effector
functions are mediated by short-acting soluble
mediators, called cytokines
These includes the previously designated
lymphokines (lymphocyte-derived) monokines
(monocyte-derived) and several other
polypeptides that regulate the immunologic,
inflammatory, and reparative host responses
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Cytokines
Most cytokines have a wide spectrum of effects,
and some are produced by several different cell
types.
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5 Types of Cytokines Based on Their General
Properties
Cytokines that mediate natural immunity
Cytokines that regulate lymphocyte growth,
activation, and differentiation
Cytokines that activate inflammatory cells
Cytokines that affect leukocyte movement
Cytokines that stimulate hematopoiesis
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Cytokines
IL-1, tumor necrosis factor-alpha (TNF-a) type 1
interferons IL-8 IL-2 IL-4 IL-5 IL-12 transfor
ming growth factor-beta (TGF-b) IL-10
IFN-g lymphotoxin (TNF-b) migration inhibitory
factor colony-stimulating factors (CSFs)
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General Properties of Cytokines
Many individual cytokines are produced by several
different cell types. For example, IL-1 and TNF-a
can be produced by virtually any cell.
The effects of cytokines are pleiotropic They
act on many cell types. For example, IL-2,
initially discovered as a T-cell growth factor,
is known to affect the growth and differentiation
of B cells and NK cells as well.
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General Properties of Cytokines
Cytokines induce their effects in three ways
they act on the same cell that produces them
IL-2 produced by activated T cells promotes
T-cell growth they affect other cells in their
vicinity IL-7 produced by marrow stromal cells
promotes the differentiation of B-cell
progenitors in the marrow they affect many cells
systemically IL-1 and TNF-a, which produce the
acute-phase response during inflammation.
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General Properties of Cytokines
Cytokines mediate their effects by binding to
specific high-affinity receptors on their target
cells
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Cytokine Network
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Immune Mechanisms
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Contact with antigen leads not only to induction
of a protective immune response, but also to
reactions that can be damaging to tissues
An antigen is a substance that can be
specifically recognized by the immune system and
cause a response
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This response may be
Production of an Antibody (Humoral) Cell to Cell
cytolysis (CMI) Tissue Damage (Hypersenstivity) A
Combination of These
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An antigen is usually a protein (gt10,000
daltons), and each antigen usually has a set of
antigenic determinants, called epitopes.
The epitope is sequence of amino acids that is
recognized by the antibody and is the site of
antibody binding to the antigen. Thus antibodies
bind (are specific for) the antigenic
determinant, rather than to the whole antigen
molecule.
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An antigen is also recognized by T-Cells, through
the binding of the antigen with the Class I MHC
molecules, and then the recognition of the
antigen-MCH protein complex by the T cell surface
receptor
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Antibody Production
Antibody production involves cell interaction
between T cells and antigen processing cells(APC)
, and then between these primed T cells and B
cells
However, some antigens can induce antibody
production without the T cell interaction. These
are called T-cell independent antigens, and occur
much less often than the T-cell dependent antigen
driven antibody responses
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Antibody production
Antigen Processing and Presentation
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T-Cell Independent
Antibody production
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T-Cell Dependent
Antibody production
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Cell to Cell cytolysis (CMI)
Killer Cell
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Tissue Damage (Hypersenstivity)
Tissue-damaging immune reactions may be evoked
not only by exogenous antigens, but also by those
that are intrinsic to the body (endogenous)
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Tissue Damage (Hypersenstivity)
Hypersensitivity diseases can be classified on
the basis of the immunologic mechanism that
mediates the disease.
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Tissue Damage (Hypersenstivity)
Type I Disease(Anaphylactic)the immune response
releases vasoactive and spasmogenic substances
that act on vessels and smooth muscle, thus
altering their function. This type is an IgE
driven Mast cell degranulation
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Tissue Damage (Hypersenstivity)
Type II Disorders, humoral antibodies
participate directly in injuring cells by
predisposing them to phagocytosis or lysis.
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Tissue Damage (Hypersenstivity)
Type III Disorders (immune complex diseases)
humoral antibodies bind antigens and activate
complement. The fractions of complement then
attract neutrophils, which, partly through the
release of neutrophilic lysosomal enzymes,
produce tissue damage.
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Tissue Damage (Hypersenstivity)
Type IV Disorders tissue injury in which
cell-mediated immune responses with sensitized
lymphocytes are the cause of the cellular and
tissue injury.
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Type I Hypersensitivity (Anaphylactic Type)
A rapidly developing immunologic reaction
occurring within minutes after the combination of
an antigen with antibody bound to mast cells or
basophils in individuals previously sensitized to
the antigen. It may occur as a systemic disorder
or as a local reaction
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Type I Hypersensitivity (Anaphylactic Type)
The systemic reaction usually follows an
intravenous injection of an antigen to which the
host has already become sensitized. Often within
minutes a state of shock is produced, which is
sometimes fatal.
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Type I Hypersensitivity (Anaphylactic Type)
Local reactions depend on the portal of entry of
the allergen and take the form of localized
cutaneous swellings (skin allergy, hives), nasal
and conjunctival discharge (allergic rhinitis and
conjunctivitis), hay fever, bronchial asthma, or
allergic gastroenteritis (food allergy)
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Type I Hypersensitivity (Anaphylactic Type)
Mast cells and basophils are central to the
development of type I hypersensitivity
They are found predominantly near blood vessels
and nerves and in subepithelial sites, where
local type I reactions tend to occur
Mast cell cytoplasm contains membrane-bound
granules that possess a variety of biologically
active mediators
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Type I Hypersensitivity (Anaphylactic Type)
Mast cells and basophils are activated by the
cross-linking of high-affinity IgE Fc
receptors Mast cells may also be triggered by
several other stimuli, such as complement
components C5a and C3a (anaphylatoxins),
macrophage-derived cytokines (e.g., IL-8), some
drugs such as codeine and morphine, mellitin
(present in bee venom), and physical stimuli
(e.g., heat, cold, sunlight).
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Type I Hypersensitivity (Anaphylactic Type)
Type I reactions are mediated by IgE antibodies.
An allergen stimulates B lymphocyte production of
IgE. This process requires the assistance of the
TH2 subset of CD4 helper T cells. IgE antibodies
formed in response to an allergen have a strong
tendency to attach to mast cells and basophils,
which possess high-affinity receptors for the Fc
portion of IgE
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Type I Hypersensitivity (Anaphylactic Type)
When a mast cell or basophil, bound with
cytophilic IgE antibodies, is re-exposed to the
specific allergen, a series of reactions takes
place, leading eventually to the release of a
variety of powerful mediators responsible for the
clinical expression of type I hypersensitivity
reactions
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Type I Hypersensitivity (Anaphylactic Type)
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Type I Hypersensitivity (Anaphylactic Type)
The bridging of IgE molecules leads to steric
hindrance of the IgE Fc receptors and initiates
two parallel and interdependent processes one
leading to mast cell degranulation with discharge
of preformed (primary) mediators and the other
involving de novo synthesis and release of
secondary mediators, such as arachidonic
metabolites
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Type I Hypersensitivity (Anaphylactic Type)
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Type I Hypersensitivity (Anaphylactic Type)
Clinical Manifestations
Systemic Anaphylaxis
Within in minutes, itching (puritis) hives, skin
erythema appear, followed shortly by extreme
difficulty in breathing due to bronchiole
constriction
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Type I Hypersensitivity (Anaphylactic Type)
Clinical Manifestations
Systemic Anaphylaxis
The lung is the principal, due to pulmonary blood
vessel smooth muscle contraction, and
hypersecretion of mucus Laryngeal edema may
obstruct the upper airway
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Type I Hypersensitivity (Anaphylactic Type)
Clinical Manifestations
Local Anaphylaxis
These are usually confined to the skin and
mucosal surfaces, when they are the source of the
antigenic exposure
On the skin, the reaction is hives or uticaria
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Type I Hypersensitivity (Anaphylactic Type)
Clinical Manifestations
Local Anaphylaxis
The itchy, erythematous welts, typical of acute
urticaria can occur in any distribution in the
body. Infants may develop facial wheals on
contact with food. Adults often have a single
bout of hives when they encounter an unusual or
seasonal food or take a drug. Hives following a
strawberry feed in the summer or after a eating
prawns at a sea-food restaurant are typical
examples
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Type I Hypersensitivity (Anaphylactic Type)
Susceptibility to Type I reactions, is called
atopy, and indicates a familial predisposition to
such localized reactions
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Type I Hypersensitivity (Anaphylactic Type)
These type reactions also have a protective
benefit parasites
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Type II Hypersensitivity (Antibody Dependent)
This type is mediated by antibodies directed
toward antigens present on the surface of cells
or other tissue components.
The antigenic determinants may be intrinsic to
the cell membrane, or they may take the form of
an exogenous antigen adsorbed on the cell
surface. In either case, the hypersensitivity
reaction results from the binding of antibodies
to normal or altered cell-surface antigens
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Type II Hypersensitivity (Antibody Dependent)
Three different antibody-dependent mechanisms
involved in this type of reaction
Complement-Dependent Reactions Antibody-Dependent
Cell-Mediated Cytotoxicity Antibody-Mediated
Cellular Dysfunction
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Complement-Dependent Reactions
1
Antibody (IgM or IgG) reacts with an antigen
present on the surface of the cell, causing
activation of the complement system and resulting
in the assembly of the membrane attack complex
that disrupts membrane integrity by drilling
holes through the lipid bilayer
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Complement-Dependent Reactions
2
Cells become susceptible to phagocytosis by
fixation of antibody or C3b fragment to the cell
surface (opsonization).
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Complement-Dependent Reactions
This type, Type II commonly involves RBC (1)
transfusion reactions (2) erythroblastosis
fetalis (3) autoimmune hemolytic anemia,
agranulocytosis, or thrombocytopenia, in which
individuals produce antibodies to their own blood
cells (4) certain drug reactions, in which
antibodies are produced that react with the drug,
which may be complexed to red cell antigen.
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Complement-Dependent Reactions
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Antibody-Dependent Cell-Mediated Cytotoxicity
This form of antibody-mediated cell injury does
not involve fixation of complement but instead
requires the cooperation of leukocytes. The
target cells, coated with low concentrations of
IgG antibody, are killed by a variety of
nonsensitized cells that have Fc receptors
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Antibody-Dependent Cell-Mediated Cytotoxicity
ADCC may be mediated by monocytes, neutrophils,
eosinophils, and NK cells.
Most often IgG antibodies are involved in ADCC,
in certain cases IgE antibodies are utilized.
ADCC may be relevant to the destruction of
targets too large to be phagocytosed, such as
parasites or tumor cells,
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Antibody-Dependent Cell-Mediated Cytotoxicity
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Antibody-Mediated Cellular Dysfunction
In some cases, antibodies directed against cell
surface receptors impair or dysregulate function
without causing cell injury or inflammation.
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Antibody-Mediated Cellular Dysfunction
Myasthenia gravis antibodies reactive with
acetylcholine receptors in the motor end plates
of skeletal muscles impair neuromuscular
transmission and therefore cause muscle weakness
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Antibody-Mediated Cellular Dysfunction
The converse, i.e., antibody-mediated stimulation
of cell function, is noted in Graves disease.
In this disorder, antibodies against the
thyroid-stimulating hormone (TSH) receptor on
thyroid epithelial cells stimulate the cells,
resulting in hyperthyroidism.
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Graves disease
Graves disease is the most common cause of
hyperthyroidism
Graves disease is a form of autoimmune disorder
that presents with symptoms of hyperthyroidism,
diffuse enlargement of the thyroid gland, and
exophthalmos (protuberant, staring eyes due to
expansion of retro-orbital soft tissue, mainly
expansion of adipose tissue)
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Graves Disease
Female 20-40yo Exophthalmos Enlarged
thyroid gland Weight Loss Nervousness
Fine tremor of the hands
Tachycardia Increased
sensitivity to heat Increased T4
Decreased TSH
Positive for TSIs
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Graves disease
The disease is due to the presence of an IgG
antibody,(TSI) originally called LATS , which
acts directly on thyroid follicle cells,
stimulating them to divide (to produce increased
cell numbers hyperplasia) and to synthesize and
secrete TH continuously, out of the control of
TSH from the pituitary.
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Graves disease
There is a high incidence of the HLA antigen
HLA-DR3 in patients with Graves disease.
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Type III Hypersensitivity (Immune
Complexmediated)
These reaction are induced by antigen-antibody
complexes that produce tissue damage as a result
of their capacity to activate a variety of serum
mediators, principally the complement system.
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Type III Hypersensitivity (Immune
Complexmediated)
However, the formation of antigen-antibody
complexes in the circulation does not imply the
presence of disease because immune complexes are
formed during many immune responses and may
perhaps represent a normal mechanism of antigen
removal
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Type III Hypersensitivity (Immune
Complexmediated)
Two general types of antigens cause immune
complexmediated injury
(1) The antigen may be exogenous, such as a
foreign protein, a bacterium, or a virus (2)
under some circumstances, the individual can
produce antibody against self component
endogenous antigens
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Type III Hypersensitivity (Immune
Complexmediated)
Immune complex diseases can be generalized, if
immune complexes are formed in the circulation
and are deposited in many organs or
localized to particular organs, such as the
kidney (glomerulonephritis), joints (arthritis),
or the small blood vessels of the skin if the
complexes are formed and deposited locally (the
local Arthus reaction)
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Type III Hypersensitivity (Immune
Complexmediated)
Acute serum sickness is the prototype of a
systemic immune complex disease
Acute serum sickness was a frequent sequel to the
administration of large amounts of foreign serum
(e.g., horse antitetanus serum) used for passive
immunization
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Type III Hypersensitivity (Immune
Complexmediated)
The pathogenesis of systemic immune complex
disease can be resolved into three phases
(1) formation of antigen-antibody complexes in
the circulation (2) deposition of the immune
complexes in various tissues, initiating (3) an
inflammatory reaction in dispersed sites
throughout the body
120
Type III Hypersensitivity (Immune
Complexmediated)
The factors that determine whether immune complex
formation will lead to tissue deposition and
disease are not fully understood, but two
possible influences are the size of the immune
complexes and the functional status of the
mononuclear phagocyte system (MPS)
121
Type III Hypersensitivity (Immune
Complexmediated)
Very large complexes formed in great antibody
excess are rapidly removed from the circulation
by the MPS cells and are therefore relatively
harmless.
The most pathogenic complexes are of small or
intermediate size (formed in slight antigen
excess), circulate longer, and bind less avidly
to phagocytic cells
122
Type III Hypersensitivity (Immune
Complexmediated)
Because the mononuclear phagocyte system normally
filters out the circulating immune complexes, its
overload or intrinsic dysfunction increases the
probability of persistence of immune complexes in
circulation and tissue deposition.
123
Type III Hypersensitivity (Immune
Complexmediated)
For reasons that are not clear the most common
(favored) sites for immune complex deposition are
renal glomeruli, joints, skin, heart, serosal
surfaces, and small blood vessels.
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Type III Hypersensitivity (Immune
Complexmediated)
For complexes to leave the microcirculation and
deposit within or outside the vessel wall, an
increase in vascular permeability must occur
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Type III Hypersensitivity (Immune
Complexmediated)
IgE antibody induced by the antigen binds to
circulating basophils and releases histamine and
PAF,which separate the endothelial cells and
allow the complexes to enter the vessel
wall immune complexes bind to inflammatory cells
through their Fc or C3b receptors and trigger
release of vasoactive mediators as well as
permeability-enhancing cytokines
126
Type III Hypersensitivity (Immune
Complexmediated)
Once complexes are deposited in the tissues, they
initiate an acute inflammatory reaction It is
during this phase (approximately 10 days after
antigen administration) that clinical features
such as fever, urticaria, arthralgias, lymph node
enlargement, and proteinuria appear.
127
Type III Hypersensitivity (Immune
Complexmediated)
The morphologic consequences of immune complex
injury are dominated by acute necrotizing
vasculitis, with deposits of fibrinoid and
intense neutrophilic exudation permeating the
entire arterial wall
128
Local Immune Complex Disease (Arthus
Reaction)
The Arthus reaction is a localized area of tissue
necrosis resulting from acute immune complex
vasculitis, usually elicited in the skin
129
Type IV Hypersensitivity (Cell-Mediated)
This type of hypersensitivity is initiated by
specifically sensitized T lymphocytes, rather
than by antibodies
It includes the classic delayed-type
hypersensitivity reactions initiated by CD4 T
cells and direct cell cytotoxicity mediated by
CD8 T cells
130
Type IV Hypersensitivity (Cell-Mediated)
It is the principal pattern of immunologic
response to a variety of intracellular
microbiologic agents, viruses, fungi, protozoa,
and parasites. So-called contact skin
sensitivity to chemical agents and graft
rejection are other instances of cell-mediated
reactions.
131
Type IV Hypersensitivity (Cell-Mediated)
Delayed-Type Hypersensitivity
The classic example of this is the TB test, the
Mantoux reaction which is produced by the
intracutaneous injection of tuberculin, a
protein-lipopolysaccharide component of the
tubercle bacillus. In a sensitized individual,
reddening and induration of the site appear in 8
to 12 hours, peak in 24 to 72 hours, and slowly
subside
132
Type IV Hypersensitivity (Cell-Mediated)
T Cell mediated Cytotoxicity
In this variant of type IV hypersensitivity,
sensitized CD8 T cells kill antigen-bearing
target cells. Such effector cells are called
cytotoxic T lymphocytes (CTLs).
133
Type IV Hypersensitivity (Cell-Mediated)
T Cell mediated Cytotoxicity
CTLs, directed against cell surface
histocompatibility antigens, play an important
role in graft rejection and in resistance to
virus infections
134
Type IV Hypersensitivity (Cell-Mediated)
T Cell mediated Cytotoxicity
In a virus-infected cell, viral peptides
associate with the class I molecules within the
cell, and the two are transported to the cell
surface in the form of a complex. It is this
complex that is recognized by cytotoxic CD8 T
lymphocytes. The lysis of infected cells before
viral replication is completed leads in due
course to the elimination of the infection
135
Type IV Hypersensitivity (Cell-Mediated)
T Cell mediated Cytotoxicity
Also many tumor-associated antigens may also be
similarly presented on the cell surface. CTLs
therefore may also be involved in tumor immunity.
136
Summary of Immune Mechanisms
Type I Anaphylactic Anaphylaxis IgE Type
II Cytotoxic Rh Disease Abs Goodpasture'
s Type III Immune Complex Arthus Rx Ag-Ab
Serum Sickness Type IV Cell Mediated TB
T Cells Contact dermatitis
Transplant rejection
137
Transplant Rejection
Graft rejection depends on recognition by the
host of the grafted tissue as foreign. The
antigens responsible for such rejection in humans
are those of the major histocompatibility antigen
(HLA) system. Rejection is a complex process in
which both cell-mediated immunity and circulating
antibodies play a role
138
Transplant Rejection
Mechanisms involve both cell and antibody
mediated reactions
139
Graft-versus-Host (GVH) Disease
GVH disease occurs when immunologically competent
cells are transplanted into immunologically
crippled recipients. GVH disease occurs most
commonly in the setting of allogeneic bone marrow
transplantation but may also follow
transplantation of solid organs rich in lymphoid
cells (e.g., the liver) or following transfusion
of unirradiated blood
140
Autoimmune Diseases
Three requirements for autoimmunity (1) the
presence of an autoimmune reaction (2) clinical
or experimental evidence that such a reaction is
not secondary to tissue damage but is of primary
pathogenetic significance (3) the absence of
another well-defined cause of the disease
141
Immunologic Tolerance
Immunologic tolerance is a state in which the
individual is incapable of developing an immune
response to a specific antigen
Self-tolerance refers to lack of responsiveness
to an individuals antigens
142
Immunologic Tolerance
How is self tolerance maintained ?
clonal deletion clonal anergy peripheral
suppression
143
Clonal Deletion
This refers to loss of self-reactive T and B
lymphocytes during their maturation
T-cells and B-cells with receptors for self
antigen are deleted in the thymus, or negatively
selected
144
Clonal Anergy
This refers to prolonged or irreversible
functional inactivation of lymphocytes, induced
by encounter with antigens under certain
conditions
145
Clonal Anergy
Activation of antigen-specific CD4 cells
requires two signals recognition of peptide
antigen in association with class II MHC
molecules on the surface of antigen-presenting
cells (APCs) and a set of second co-stimulatory
signals provided by APCs.
If the antigen is presented by cells that do not
bear the CD28 ligand, a negative signal is
delivered, and the cell becomes anergic
146
Peripheral suppression by T cells
Many factors, both cellular and humoral, that can
actively suppress autoreactive lymphocytes have
been described. Suppressor T cells. These cells,
like cytotoxic T cells, are CD8 but are believed
to comprise a distinct subset.
147
Mechanisms of Autoimmune Diseases
The pathogenesis of autoimmunity appears to
involve immunologic, genetic, and viral factors
interacting through complicated mechanisms that
are poorly understood
148
Mechanisms of Autoimmune Diseases
Loss of Tolerance
Bypass of Helper T Cell Tolerance Molecular
Mimicry Polyclonal Lymphocyte Activation Imbalance
of Suppressor-Helper T-Cell Function Emergence
of a Sequestered Antigen
149
Bypass of Helper T Cell Tolerance
Tolerance may be broken if the need for helper T
cells is bypassed
Modification of a self antigen, originally
recognized as self is now recognized as non self
Expression of costimulatory molecules the
second signal
150
Molecular Mimicry
Several infectious agents cross-react with human
tissues through their haptenic determinants
(B-cell epitopes)
The infecting microorganisms may trigger an
antibody response by presenting the
cross-reacting haptenic determinant in
association with their own carrier, to which the
helper T cells are not tolerant
The antibody so formed may then damage the tissue
that shares the cross-reacting determinants
151
Polyclonal Lymphocyte Activation
Autoimmunity may occur if such self-reactive but
anergic clones are stimulated by
antigen-independent mechanisms
152
Imbalance of Suppressor-Helper T-Cell Function
Any loss of suppressor T-cell function will
contribute to autoimmunity, and, conversely,
excessive T-cell help may drive B cells to
extremely high levels of autoantibody production
153
Emergence of a Sequestered Antigen
Any self-antigen that is completely sequestered
during development is likely to be viewed as
foreign if introduced into the circulation, and
an immune response will develop.
Spermatozoa, myelin basic protein, and lens
crystallin may fall into this category of antigens
154
Consequences of the loss of self-toleranceauto
immune diseases
Autoimmune diseases range from those in which the
target is a single tissue, such as the autoimmune
hemolytic anemias and thyroiditis, to those in
which a host of self-antigens evoke a
constellation of reactions against many organs
and systems
155
Systemic Lupus Erythematosus (SLE)
SLE is the a multisystem disease of autoimmune
origin, characterized by a many autoantibodies,
particularly antinuclear antibodies (ANAs).
Acute or insidious in its onset, it is a chronic,
remitting and relapsing, often febrile illness
characterized principally by injury to the skin,
joints, kidney, and serosal membranes. Virtually
every other organ in the body, however, may also
be affected.
156
Systemic Lupus Erythematosus (SLE)
SLE is a common disease, with a prevalence that
may be as high as 1 in 2500 in certain
populations Like most autoimmune diseases, SLE is
predominantly a disease of women, with a
frequency of 1 in 700 among women between the
ages of 20 and 64 and a female-to-male ratio of
91.
157
Systemic Lupus Erythematosus (SLE)
The disease is more common and severe in American
black women (1 in 245). Although SLE usually
arises in the second and third decades, it may
become manifest at any age, even in early
childhood.
158
Systemic Lupus Erythematosus (SLE)
The cause of SLE remains unknown, but the
existence of a many number of antibodies in these
patients against self-constituents indicates that
the fundamental defect in SLE is a failure of the
regulatory mechanisms that sustain self-tolerance
159
Sjögrens Syndrome
Sjögrens syndrome is characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from immunologically
mediated destruction of the lacrimal and salivary
glands.
160
Sjögrens Syndrome
It occurs as an isolated disorder (primary form),
also known as the sicca syndrome, or more often
in association with another autoimmune disease
(secondary form). Among the associated
disorders, rheumatoid arthritis is the most
common, but some patients have SLE, polymyositis,
scleroderma, vasculitis, mixed connective tissue
disease, or thyroiditis
161
Sjögrens Syndrome
Approximately 90 of patients with Sjögrens
syndrome are women between the ages of 40 and 60
years. The keratoconjunctivitis produces
blurring of vision, burning, and itching, and
thick secretions accumulate in the conjunctival
sac. The xerostomia results in difficulty in
swallowing solid foods, a decrease in the ability
to taste, cracks and fissures in the mouth, and
dryness of the buccal mucosa.
162
Systemic Sclerosis (Scleroderma)
Characterized by excessive fibrosis throughout
the body. The skin is most commonly affected, but
the gastrointestinal tract, kidneys, heart,
muscles, and lungs also are frequently involved
163
Systemic Sclerosis (Scleroderma)
In some patients, the disease appears to remain
confined to the skin for many years, but in the
majority, it progresses to visceral involvement
with death from renal failure, cardiac failure,
pulmonary insufficiency, or intestinal
malabsorption.
164
Systemic Sclerosis (Scleroderma)
systemic sclerosis has two major categories
diffuse scleroderma, characterized by widespread
skin involvement at onset, with rapid progression
and early visceral involvement, localized
scleroderma, associated with relatively limited
skin involvement often confined to fingers,
forearms, and face. Visceral involvement occurs
late hence, the clinical course is relatively
benign.
165
Systemic Sclerosis (Scleroderma)
Many of these patients have the CREST syndrome.
Calcinosis Raynauds phenomenon Esophageal
dysmotility Sclerodactyly Telangiectasia
166
Calcinosisdeposition of calcium salts in body
tissues
Raynauds phenomenonintermittent attacks of
pallor or cynaosis especially of the fingers, due
to vasospasm, often precipitated by exposure to
cold. Fingers are first white due to cold, then
blue due to dilation and stagnation, then red due
to vasodilation
Esophageal dysmotility difficulty in swallowing
due to fibrosis
Sclerodactyly Scleroderma or fibrosis of the
digits of the finger
Telangiectasiadilation of the capillaries and
formation of an angioma
167
Immunologic Deficiency Syndromes
Traditionally, immunodeficiency disorders are
considered according to the primary component or
components involved (i.e., the B cell, the T
cell, the undifferentiated stem cell, or
complement) however, in view of the extensive
cell interactions between T and B lymphocytes and
macrophages, these distinctions are not always
clear-cut
168
Immunologic Deficiency Syndromes
Immunodeficiencies can also be divided into the
primary immunodeficiency disorders, which are
almost always genetically determined, and
secondary immunodeficiency states, arising as
complications of infections malnutrition aging
or side effects of immunosuppression,
irradiation, or chemotherapy for cancer and other
autoimmune diseases
169
Immunologic Deficiency Syndromes
X-Linked Agammaglobulinemia of Bruton Common
Variable Immunodeficiency (CVI) Isolated IgA
Deficiency
DiGeorges Syndrome (Thymic Hypoplasia)
Severe Combined Immunodeficiency Diseases (SCID)
170
X-Linked Agammaglobulinemia of Bruton
This is one of the most common forms of primary
immunodeficiency and is characterized by the
virtual absence of serum immunoglobulins and is
restricted to males
B cells are virtually absent in the blood
171
Common Variable Immunodeficiency (CVI)
This relatively common The feature common to all
patients is hypogammaglobulinemia, generally
affecting all the antibody classes Most patients
with common variable immunodeficiency (CVI) have
normal numbers of B cells in the blood and
lymphoid tissues but these B cells, however, are
not able to differentiate into plasma cells
172
Isolated IgA Deficiency
Isolated IgA deficiency is a very common
immunodeficiency. In the United States, it occurs
in about 1 in 600 individuals
Most individuals with this disease are completely
asymptomatic
173
Isolated IgA Deficiency
Because IgA is the major immunoglobulin in
external secretions, mucosal defenses are
weakened, and infections occur in the
respiratory, gastrointestinal, and urogenital
tracts. Symptomatic patients commonly present
with recurrent sinopulmonary infections and
diarrhea
The basic defect is in the differentiation of IgA
B lymphocytes
174
DiGeorges Syndrome (Thymic Hypoplasia)
This is an example of selective T-cell deficiency
that derives from failure of development the
thymus
Thus, these patients have total absence of
cell-mediated immune responses
Absence of cell-mediated immunity is reflected in
low levels of circulating T lymphocytes and a
poor defense against certain fungal and viral
infections
175
Severe Combined Immunodeficiency Diseases (SCID)
This group of immunodeficiency diseases is
characterized by combined T-cell and B-cell
defects.
Affected infants are susceptible to recurrent,
severe infections by a wide range of pathogens,
including Candida albicans, Pneumocystis carinii,
Pseudomonas, cytomegalovirus, varicella, and a
whole host of bacteria
176
Severe Combined Immunodeficiency Diseases (SCID)
Without bone marrow transplantation, death occurs
within the first year of life
The defect resides in the T-cell compartment,
with a secondary impairment of humoral immunity.