Far Eastern University Nicanor Reyes Medical Foundation

Pathology A Immune Disorders (Part 1)

Aida Lat M.D.
Immune System
Serves as protection for pathogens abound in the environment.
However, the immune system itself is capable of causing tissue
injury and disease.
Allergies
Autoimmune disorders
The mechanism of defense against microbes fall into two broad
categories: Innate and Adaptive Immunity.
INNATE IMMUNITY
Also called Natural or Native Immunity.
A mechanism that is ready to react to infections even before
they occur.
It has evolved to specifically recognize and combat microbes.
Innate Immunity functions in different stages:
Recognition of the microbes or damaged cells
Activation of various mechanisms
Elimination of unwanted substances
Components of the Innate Immunity
1.) Epithelial Barriers
The skin and the lining of the GIT and Respiratory tract provide
mechanical barriers to the entry of microbes.
It also produces antimicrobial molecules such as defensins.
Lymphocytes located in the epithelia also combat microbes.

6.) Innate Lymphoid Cells

Cells with the appearance of Lymphocytes but with the features
more like the cells of innate immunity.
Contributes early defense against microbes.
7.) Soluble Proteins
Complement System
Classic Pathway activated by Ag-Ab complex
Lectin Pathway activated by mannose on bacterial surface
Alternative Pathway activated by microbial surface
The innate immune response is mediated by alternative and
lectin pathways, while the adaptive immune response is
mediated by the classical pathway.
Mannose-Binding Protein and C - reactive protein coat microbes
and promote phagocytosis.
Lung surfactant is also a component of the innate immunity,
providing protection against inhaled microbes.
Cellular Receptors
Pathogen-Associated Molecular Pattern (PAMPs)
Molecules associated with groups of pathogens that are
recognized by the cells of the innate immunity.
Damage-associated Molecular Pattern (DAMPs)
Molecules released by injured and necrotic cells recognized by
leukocytes.
Cell receptors that recognize these molecules are called as
Pattern Recognition Receptors.
These receptors are located in all the cellular compartments.
TOLL-LIKE RECEPTORS (TLR)

2.) Phagocytic Cells

Monocytes and neutrophils are phagocytes present in the blood.
Monocytes that enter tissues & mature are called macrophages.
These cells not only sense the presence of offending agents but
they also ingest (phagocytose) these invaders and destroy them.
3.) Dendritic Cells
Specialized cell population present in the epithelia, lymphoid
organs, and most tissues.
They capture proteins and display peptides for T Cell recognition
They have rich collection of receptors that sense microbes and
cell damage.
They also stimulate the secretion of cytokines and mediators
that play critical roles in inflammation and anti-viral defense.
Dendritic cells are involved in the initiation of the innate immune
response but they are not part of destruction of offending agent
4.) Natural Killer Cells (NK Cells)
Provide early protection against viruses and intracellular bacteria
5.) Mast Cells
Capable of producing mediators of inflammation.

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Discovered in Drosophila.
There are 10 TLRs in mammals; each recognizes a different set of
microbial molecules.
Present in the Plasma Membrane & in Endosomal Membrane.
All receptors signal by a common pathway that culminates in the
activation of two sets of transcription factors:

1.) NF-kB
Stimulates the synthesis and release of cytokines.
Expression of adhesion molecules.
Both of which are critical for the recruitment and activation of
leukocytes.
2.) Interferon Regulating Factors (IRF)
Stimulates the production of the anti-viral cytokines (Type 1 IFN)
Germline loss-of-function mutations affecting TLRs and their
signaling pathways are associated with rare but serious
immunodeficiency syndromes.
NOD-LIKE RECEPTORS AND THE INFLAMMASOME

OTHER RECEPTORS FOR MICROBIAL PRODUCTS

C-type Lectin Receptors (CLRs)
Expressed on the plasma membrane of dendritic cells that
detect fungal glycans and elicit inflammatory reaction
against fungi.
Rig-Like Receptors (RLR)
Located in the cytosol.
Detect nucleic acids of viruses that replicate in the
cytoplasm of the infected cells.
These receptors stimulate the production of anti-viral
cytokines.
G-Protein Coupled Receptors
Those found in most leukocytes can recognize short
bacterial peptides containing N-formylmethionyl residues.
These receptors enable the neutrophils to detect bacterial
proteins and stimulate chemotactic response of the cells.
Mannose Receptors
Recognize microbial sugars which often contain mannose
residues and induce phagocytosis of the microbes.
REACTIONS OF THE INNATE IMMUNITY
The innate immunity provides defense by two main reactions:
Inflammation cytokines and products of the complement
activation triggers the vascular and cellular components of
the inflammatory process.
Anti-viral defense Type 1 Interferons produced in
response to viruses act on infected and uninfected cells,
and activates enzymes that degrade viral nucleic acid.
The innate immune system may also provide danger signals
to stimulate the adaptive immune response.

NLRs are cytosolic receptors that recognize a wide variety of

substances, including products of necrotic cells (e.g. uric acid,
released ATP), ion disturbances (e.g. loss of K+), and some
microbial products.
Mechanism of detection by this sensor is not known.
The NLR signal a multiprotein complex called the Inflammasome
The inflammasome activates caspase-1 that cleaves a precursor
of IL-1 to generate a biologically active form of IL-1.
IL-1 is a mediator of inflammation that recruits leukocytes and
induces fever.
Gain-of-function mutations in one of the NLRs result in periodic
fever symptoms called autoinflammatory syndromes.
This syndrome responds very well to treatment with IL-1
antagonists.
NLR-Inflammasome pathway play a role in many common
disorders such as:
Recognition of urate crystals in gout
Detection of lipids and cholesterol crystals that are
abnormally deposited in the tissues that may result in
inflammation in obesity-associated DM type 2 and
Atherosclerosis.

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Innate immunity does not have memory or fine antigen specificity, it

uses 100 different receptors to recognize 1,000 molecular patterns. In
contrast, the adaptive immunity uses two types of receptors (Antibodies
and T-Cell Receptors), each with millions of variations that recognize
millions of antigens.

ADAPTIVE IMMUNITY
Also called Acquired or Specific immunity.
Mechanisms that are stimulated by or adapt to microbes and are
capable of recognizing microbial and non-microbial substances.
Usually develops later after exposure to the agents.
The term Immune Response refers to the adaptive immunity.
Consist of lymphocytes and their products (including Antibodies).
There are two types of adaptive immunity:
Humoral
Mediated by B-lymphocytes (from Bone marrow)
Function against extracellular microbes and toxins
These secrete antibodies (also known as Immunoglobulins)
Cell-Mediated
Mediated by T-lymphocytes (from Thymus)
Function against intracellular microbes.
Both classes have highly specific receptors for a wide variety of
substances called Antigens.

CELLS OF THE IMMUNE SYSTEM

B and T lymphocytes are morphologically unimpressive, but they
are actually remarkably heterogeneous and specialized in
molecular properties and functions.
Lymphocytes and other cells involved in the immune system are
not fixed in a particular tissue but constantly circulate among
lymphoid and other tissues via the lymphatic circulation.
This allows immune surveillance of the lymphocytes.
In lymphoid organs, the different classes of lymphocytes are
arranged in such way that they interact with one another only
when stimulated.
Nave Lymphocytes are matured lymphocytes that have
not encountered the antigen for which they are specific.
Effector Cells are nave lymphocytes that are activated by
recognition of antigens and other signals.
Memory Cells Live in a state of heightened awareness and
are able to react rapidly and strongly upon re-exposure.

T-LYMPHOCYTES
There are 3 major population of T-lymphocytes:
1. Helper T-lymphocytes
2. Cytotoxic T-lymphocytes
3. Regulatory T-lymphocytes
60-70% of population of lymphocyte in the blood.
Produced in the bone marrow but matures in the thymus.
Recognizes a specific cell-bound antigen by means of an antigenspecific TCR (T-cell receptor), which is a disulfide-linked
heterodimer made up of and polypeptide chain.
The -TCR recognizes peptide antigens presented by the
major histocompatibility complex molecules on the surface of
the antigen presenting cells.

Lymphocyte Diversity

CLONAL SELECTION
Lymphocytes express specific receptors for antigens and
mature into functionally competent cells before exposure
to antigen.
Lymphocytes of the same specificity constitute a CLONE,
expressing identical antigen receptors.
Antigen receptor diversity is generated by somatic
recombination of the genes that encode the receptor proteins.
Lymphocytes and most cells in the body contain the AntigenReceptor gene which has spatially separated segments that
recombine in random sets and variations forming many different
genes that can be transcribed and translated to a functional
antigen receptor.
RAG-1 and RAG-2 enzymes responsible for the recombination
of antigen-receptor gene. Inherited defects result in a failure to
generate mature lymphocytes.

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MHC Restriction limits the specificity of the T-cells for peptides

displayed by the MHC molecules, ensures that T cells see only
cell-associated antigens.
CD3 and proteins
Invariant, same in all T-cells
Involved in transduction of signals into the T-cell that are
triggered by the binding of the antigen.
TCR + CD3- = TCR COMPLEX
polypeptide chains
Expressed by small population of T-cells.
Recognizes peptides, lipids, and, small molecules without
the requirement of the MHC proteins.
Tends to aggregate in mucosal and epithelial linings,
suggesting that these are sentinels that protect against
microbes that invade the epithelia.
CD4 and CD8 proteins
Acts as co-receptors in T-cell activation.
CD4 (expressed in 60%) binds to MHC II molecules, and
function as cytokine secreting helper cell that helps
macrophages and B lymphocytes.
CD8 (expressed in 30%) binds to MHC I molecules, function
as cytotoxic T-lymphocyte (CTL) that destroy cell harboring
microbes.
Integrins adhesion molecules that attaches T-cell to APC.
CD28 binds to CD80 or CD86 in the APC.

B-LYMPHOCYTES

MACROPHAGES

The only cell that can produce antibodies which are mediators of
the humoral immunity.
Develop and mature in the bone marrow, constitutes 10-20% of
the population of the circulating lymphocytes.
Present in peripheral lymphoid tissues such as spleen, lymph
nodes, and mucosa-associated lymphoid tissues.
IgM and IgD isotypes are present in the surface of nave B cells,
which serves as its antigen-binding component.

Part of the mononuclear phagocyte system.

Important functions in the induction and effector phases of the
adaptive immune response:
Antigen-presenting cell for T-cell activation.
Effector cells that eliminate microbes upon activation by Tcells which enhance their ability to kill ingested microbes.
Phagocytose and destroy microbes that are opsonized or
coated by IgG or C3b.

NATURAL KILLER CELLS (NK Cells)

After stimulation, it matures to a Plasma Cell which produces Ab

Antibody-secreting cells detected in the peripheral blood of
human are called plasmablasts.
The receptor also contains a heterodimer of two invariant
protein Ig (CD79a) and Ig (CD79b), which are essential for
signal transduction through the antigen receptor.
CR2 or CD21 is a type-2 complement receptor which recognizes
complement products during innate immune response to
microbes.
CD40 receives signals from Helper T-cells.
CR2 is used by the Epstein - Barr virus to enter and infect B Cells.

Function is to destroy irreversible stressed and abnormal cells.

Make up approximately 5-10% of the peripheral lymphocytes.
Do not express TCR or Igs.
NK cells are larger and contain abundant azurophilic granules.
Can kill variety of virus-infected cells and tumor cells without
prior exposure to or activation by microbes or tumors.
Surface molecules used to identify NK Cells:
CD16 Fc receptor for IgG, confers the NK cells ability to
lyse IgG coated targets, known as the antibody-dependent
cell-mediated cytotoxicity (ADCC).
CD56 Unknown function.
The NK Cell is regulated by balance between activating and
inactivating signals from the receptors.
NKG2D activating receptor that recognizes surface
molecules induced by various stressors.
NK inhibitory cell receptors recognize self MHC I molecules
which are expressed in all healthy cells, which prevents NK
Cells from killing normal cells.

DENDRITIC CELLS
Sometimes called Interdigitating Dendritic Cells.
The most important antigen-presenting cell for initiating T-cell
response against protein antigens.
Have numerous fine cytoplasmic processes.
These cells are located under the epithelia and interstitium ,
which is a common site of entry of antigens and microbes to
capture them. (Langerhan Cells immature dendritic cells within
the epidermis)
Express many receptors (e.g. TLRs and Lectins) for capturing
These cells are recruited to the T-cell zones of the lymphoid
organs to present the captured antigens to the T-cells.
These cells also express high levels of MHC needed for antigenpresentation.
Follicular Dendritic Cells are present in the germinal centers of
the lymphoid follicles which bear Fc receptors for IgG and
receptors for C3b.
They can trap antigen bound to antibodies or complement
proteins.

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NK Cells also release cytokines such as IFN- that activates

macrophages to destroy ingested microbes.
NK Cell activity is regulated by many cytokines such as:
IL-2, IL-15 stimulates proliferation of NK Cells
IL-12 activates killing and secretion of INF-

INNATE LYMPHOID CELLS (ILCs)

Population of lymphocytes that lack TCRs but produce cytokines
similar to those made by T cells.
NK cells are considered the first ILCs.
Different subsets of ILCs produce IGN-Y, IL-5, IL-17, and IL-22.
Functions have been attributed to ILCs:
Early defense against infections.
Recognition and elimination of stressed cells
Shaping the later adaptive immunity.
TISSUES OF THE IMMUNE SYSTEM

Spleen
An abdominal organ that serves the same role in immune
response to blood borne antigens because lymph nodes only
responds to lymph borne antigens.
Blood borne antigens are trapped by dendritic cells and
macrophages in the spleen.
Cutaneous and Mucosa-Associated Lymphoid Tissues
Present in the GIT, Epithelium, or the Respiratory Tract.
Respond to antigens that enter the breaches of the epithelium
Pharyngeal Tonsil and Peyers Patches of the intestines.

Within these peripheral organs, B cells and T cells are segregated

into different regions:
Lymph nodes:
B cells are concentrated in the cortex of follicles.
If the B cells have already responded to an antigen, the
follicles contain a central region called the germinal
centers.
T cells are located in the paracortex of follicles.
Spleen
T cells are located in the periarteriolar lymphoid sheaths
(PALS) surrounding small arterioles.
B cells reside in the follicles.
LYMPHOCYTE RECIRCULATION

GENERAL LYMPHOID ORGANS

Principal Generative Organs:
Thymus site of T-cell maturation
Bone Marrow site of production of all blood cells, and site
of maturation of B-cells.
PERIPHERAL LYMPHOID ORGANS
Organized to concentrate antigens, APCs, and lymphocytes in a
way that optimizes interactions among these cells and develop
the adaptive immune response.
Lymph Nodes
Nodular aggregates of tissues located along lymphatic channels.
APCs in the nodes are able to sample antigens that may enter
into the epithelia and carried in the lymphatic circulation.
Dendritic cells may also pick up and transport antigen from the
tissues to the lymph nodes via the lymphatic circulation.
Thus, these antigens become concentrated in the draining lymph
nodes.
Pathologists do not use the inguinal lymph nodes to detect pathologies
because they are drainage areas hence what are present are mostly
destroyed cells. It is preferable to get from the cervical or axillary area.

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Nave T-cells need this process because they have to circulate

through the peripheral lymphoid organs where most antigens
are concentrated.
Activated or Effector T-cells, because of antigens, go to the
peripheral circulation and exert their effects.
Plasma cells stay in the lymphoid organs and produce antibodies.

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

Displays peptide fragments of protein antigens for recognition.
MHC is a product of genes that evoke rejection of transplanted
organs, and their name derives from their role in determining
tissue compatibility.
In humans, it is called the Human Leukocyte Antigens (HLA).
HLA is highly polymorphic, meaning there are many alleles of
MHC genes in humans, except in identical twins.
CLASS I MHC
Expressed in all nucleated cells and platelets
Contains polymorphic -chain (heavy) and a non-polymorphic 2
microglobulin, chain is encoded by HLA-A, B, and C.
Displays peptides that are derived from proteins, such as viral
and tumor antigens.
Located in the cytoplasm, usually produced in the ells.
Recognized by CD8+ T Lymphocytes.
Cytoplasmic proteins are degraded by protesomes, and peptides
are transported into the Endoplasmic Reticulum.
It is in the ER where the peptide binds to synthesized class I
molecules.
The peptide-loaded MHC associates with 2 microglobulin to
form a trimer and is then transported to the cell surface.
The 3 domain has a binding site for CD8+ T Cells, which
functions as a Cytotoxic T-Cell.
This makes CD8+ Cells, Class I MHC Restricted.
CLASS II MHC
Encoded in a region called HLA-D with 3 sub-regions: HLA-DP,
HLA-DQ, and HLA-DR.
Each consist of and chain.
Class II MHC presents antigens that are internalized into vesicles
and are typically derived from extracellular microbes and
soluble proteins.
The internalized proteins are degraded by proteasomes, the
digested peptides associate with class II molecules in the
vesicles, which is then transported to the cell surface.
B2 domain has a binding site for CD4+ T-Cells which function as
Helper Cells.
This makes CD4+ T-Cells, Class II MHC Restricted.
MHC II is expressed on cells that present ingested antigens and
respond to T-cell help.

MHC I

T-Cell
CD8+

MHC II

CD4+

Site of MHC binding

Endoplasmic
Reticulum
Vesicles

Virus-infected cells
Tumor cells
Extracellular microbes
Soluble Proteins

MHC Locus also contains genes that encode some complement

components and cytokines, TNF and Lymphotoxins.

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Diseases Associated with HLA-inheritance

Inflammatory Diseases (HLA-B27)
Ankylosing Spondylitis
Inherited Errors of Metabolism
21 OH-ase deficiency
Hereditary Hemochromatosis
Autoimmune Diseases (DR Locus)
Rheumatoid Arthritis
Scleroderma
Diabetes
Hepatitis

CYTOKINES
They are messenger molecules of the immune system.
Short acting, mediators of inflammation.
Most important are Interleukins because they mediate
communications between leukocytes.
Most cytokines have a wide spectrum of effects and some are
produced from different cell types.
Cytokines contribute to:
Innate immune response. Cytokines are produced rapidly
after encounter with microbes to produce inflammation:
TNF, IL-1, IL-12, Type 1 IFN, IFN- and chemokines.
Adaptive immune response. Cytokines produced by CD4+ T
cells which are active by antigens. Functions to promote
lymphocyte proliferation and differentiation to their active
effector cells: IL-1, IL-4, IL-5, IL-17, IFN-.
Termination of immune responses: TGF-, IL-10.
Stimulate hematopoiesis: These are called Colonystimulating factors that increase leukocyte numbers during
immune and inflammatory responses to replace damaged
leukocytes: GM-CSF, IL-7
IL-1 for Fever, IL-5 for eosinophils (from recording).

LYMPHOCYTE ACTIVATION

IgA is secreted in the mucosal epithelium.

IgG is actively transported in the placenta.
IgE and eosinophils combat parasitic infections.
Most circulating IgG have a half-life of about 3 weeks, the
Antibody-secreting plasma cell migrate to the bone marrow and
live for months or even years.
Memory Cells are also generated upon activation of lymphocyte.

Cell Mediated Immunity

Nave T-Lymphocytes are activated by antigens from ingested
microbes or proteins which are presented by the APC.
Earliest response of CD4+ T-Cell is to secrete IL-2 and express
high-affinity receptors for IL-2.
IL-2 acts as a growth factor to stimulate T-Cell proliferation,
leading to an increase in number of antigen-specific T-Cells.
Some T-cells differentiate to effector cells and produce different
sets of cytokines:

HYPERSENSITIVITY

Humoral Immunity
Upon activation of the complement via the MAC system
(C5a6789), B lymphocytes proliferate and differentiate into
plasma cells that secrete different classes of antibodies with
distinct functions.
Important for the neutralization of microbes and toxins and the
function of the ADCC.
Antibodies bind to microbes and prevent them from infecting
cells.
IgG coats microbes and target them for phagocytosis, since
phagocytes (neutrophils and macrophages) express receptors for
Fc tails of the antibodies.
IgG and IgM activates the complement system via the classical
pathway.

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An excessive or harmful reaction to an antigen.

Individuals who have been previously exposed to an antigen
manifest a detectable reaction to the said antigen and therefore
said to be sensitized.
Features of hypersensitivity:
Elicited by exogenous or endogenous antigens.
Hypersensitivity to exogenous substances: Allergy
Hypersensitivity to self-antigens: Autoimmune Disease
Results from an imbalance between the effector
mechanisms of immune responses and the control
mechanisms that serve normally to limit responses.
Hypersensitivity diseases are often associated with
inheritance of susceptibility genes.
The mechanism of injury in hypersensitivity is the same as
the effector mechanism of the immune system.
TYPES OF HYPERSENSITIVITY

TYPE I HYPERSENSITIVITY (Anaphylactic)

Immediate Hypersensitivity.
Caused by TH2 cells, IgE, Mast Cells
Mast cells release mediators that act on vessels and smooth
muscles, and pro-inflammatory cytokines that recruit
inflammatory cells.
Basis for the development of allergy.
TH2 Cells produce IL-4 in response to the antigen and cause
differentiation of other T Cells to TH2 Cells.
IL-4, IL-5, IL-13 are produced.
IL-4 acts on B-cells to switch to IgE production.
IL-5 involved in the development and activation of
eosinophils.
IL-13 enhances IgE production, and acts on epithelial cells
to stimulate mucus secretion.

Mast cells have high affinity receptors called FcRI, which is

specific for the Fc portion of the IgE.
In addition, they may also be triggered by proteins of the
complement C5a and C3a which are anaphylatoxins.
IgE coated mast cells become sensitized and release:
Vasoactive amines (histamine)
Neutral proteases and acid hydrolases
Proteoglycans (Heparin) which is an anti-coagulant.
Lipid mediators, reaction in the cell membranes lead to
activation of phospholipase A2 and converts arachidonic acid to:
Leukotrienes C4 and D4 are potent vasoactive and
spasmogenic agents. B4 is chemotactic to neutrophils.
Prostaglandin D2 Intense bronchospasm, increased
mucus secretions.
Platelet-Activating Factor (PAF) not derived from
arachidonic acid, but causes platelet aggregation, release of
histamine, bronchospasm, increased vascular permeability,
and vasodilation.

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Susceptibility to immediate hypersensitivity reactions is

genetically determined.
Atopy predisposition to develop localized immediate
hypersensitivity, usually have elevated IgG and IL-4. (e.g. food,
pollens, dusts)
Non-Atopic exercise, intense temperatures, emotions.
5q31 these regions include genes encoding for IL-3, IL-4, IL-5, IL9, IL-13, and GM-CSGF, which are linked to polymorphisms in
patients with asthma.
SYSTEMIC ANAPHYLAXIS
Characterized by vascular shock, widespread edema, and
difficulty in breathing.
Food allergies, drugs, venoms.
Laryngeal edema results in hoarsness, and further
compromises breathing.
Urticaria, edema, erythema appears on localized cases.

TYPE II HYPERSENSITIVITY (Cytotoxic)

Antibodies that react with antigens present on the cell surfaces
or in the ECM causes disease by destruction of the cells
triggering inflammation or interfering with normal functions.
IgG and IgM antibodies injure cells by promoting their
phagocytosis or lysis and injure the tissues, causing
inflammation.
Mechanisms:
Opsonization and Phagocytosis
Complement- and Fc receptor-mediated inflammation
Antibody-mediated cellular dysfunction.
1.) Opsonization and Phagocytosis

Cells opsonized by the IgG antibodies are recognized by the Fc

receptors.
The IgG and IgM deposited on the cell surface may activate the
complement system generating C3b and C4b byproducts.

 These C3b and C4b byproducts are deposited in the cell surface
and are recognized by phagocytes.
The complement system also generates the Membrane attack
complex (C5a6789) which disrupts the lipid bilayer causing
osmotic lysis of the cell.
ADCC may occur when NK Cells and macrophages bind to Fc
fragments of IgG and cause cell lysis without phagocytosis.
Net result is phagocytosis of the opsonized cell and their
destruction.
This happens during:
Transfusion reactions
nd
Eryhtroblastosis Fetalis (on 2 baby)
Autoimmune anemia, agranulocytosis, thrombocytopenia
Drug reactions (Haptens)

TYPE III HYPERSENSITIVITY (Immune Complex)

IgG and IgM bind to antigens in the circulation, and the Ag-Ab
complex are deposited in the tissue inducing inflammation.
Neutrophils and Monocytes are recruited and produce tissue
damage by release of lysosomal enzymes and generation of toxic
free radicals.
Systemic Immune Complex Disease
Acute Serum Sickness is the prototype of systemic immune
disease.
1.) Formation of Immune Complex

2.) Complement- and Fc-receptor mediated inflammation

Deposited antibodies activate the complement generating byproducts such as C5a which the most potent anaphylatoxin and a
chemotactic agent.
This directs the migration of PMNs and Monocytes, which are
activated by their engagement in their C3b and Fc receptors.
Results in the production of substances that damage tissue such
as lysosomal enzymes, proteases, and ROS.
This happens during:
Glomerulonephritis
Vascular Rejections (Graft vs. host)
Goodpasture Syndrome

Protein Ag triggers an immune response that results in the

formation of Ab, typically about a week after the injection of the
protein. The Abs are secreted in the circulation where they react
with the still circulating Ags.
2.) Deposition of Immune Complexes

3.) Antibody-mediated cellular dysfunction

Antibodies directed against cell surfaces can impair or

dysregulate function without causing injury.
This happens in:
Myasthenia gravis Ach cannot bind to its receptor due to a
bound antibody.
Graves Disease the antibodies against TSH receptor
stimulate the thyroid cells causing hyperthyroidism.

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The circulating Ag-Ab complex are deposited in various tissues,

complexes that are of medium size, formed in slight antigen
excess are the most pathogenic.
Sites where blood is filtered at high pressure (e.g. urine and
synovial fluid) to form other fluids are sites where immune
complexes become concentrated and tend to deposit.
Hence these complexes are concentrated in joints and glomeruli.

3.) Inflammation and Tissue Injury

TH1 cell is associated with inflammatory reaction dominated by

activated macrophages, while TH17 triggered inflammatory
reaction is dominated by neutrophils.
CD4+ T-cells are activated by APCs and produce IL-2 that acts to
other T-cells to differentiate to TH1 or TH17.
TH1 cells release IFN- in response to prolonged and repeat
exposure to antigens. Classically activated macrophages (via IFN) express more class II MHC and secrete TNF, IL-1, and
chemokines, and more IL-12 amplifying TH1 response.
Clinical Examples of CD4+ T-Cell Mediated Reaction
Tuberculin Reaction

Upon deposition, they initiate an acute inflammatory reaction.

During this phase (approx. 10 days after administration), fever,
urticarial, arthralgia, lymph node enlargement, and proteinuria
appear.
Resultant lesion is termed
Vasculitis blood vessels
Glomerulonephritis glomerulus
Arthritis Joints.
Type III Hypersensitivity is best determined under immune
fluorescence.
Chronic Serum Sickness results from repeated and prolonged
exposure to an antigen, which occurs in several diseases such as
Systemic Lupus Erythematosus (SLE).
Arthus Reaction (Local Immune Complex Disease)
A localized area of tissue necrosis resulting from acute
immune complex vasculitis, usually elicited in the skin.

TYPE IV HYPERSENSITIVITY (Cell-mediated, Delayed)

Sensitized T-lymphocytes (TH1, TH17, CTLs) cause tissue injury.
Cell-mediated caused by inflammation resulting from cytokines
produced by CD4+ T cells and cell killing by CD8+ T cells.
CD4+ T-Cell mediated inflammation

Cytokines produced by the T cells induce inflammation that may

be chronic and destructive.
Ag administered in the skin of a previously immunized individual
result to a detectable cutaneous reaction within 24 to 48 hours.

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Produced by intra-cutaneous injection of purified protein

derivative (PPD or Tuberculin), a protein-containing antigen of
the Tubercle Bacillus.
In a previously sensitized individual, reddening and induration
appears in 8-12 hours, and peaks in 24-72 hours.
Can be characterized by accumulation of mononuclear cells and
macrophages around venules producing perivascular cuffing.
Granulomatous Inflammation
Certain persistent, non-degradable antigen such as tubercle
bacilli colonizing the lungs, the infiltrate is dominated by
macrophages for 2-3 weeks.
Sustained activation of macrophages undergoes morphologic
change to epitheloid cells.
Morphologic aggregation of epitheloid cells surrounded by a
collar of lymphocytes is called a Granuloma.
This pattern of inflammation is associated with TH1 activation
and high level production of IFN-.
Contact Dermatitis
It maybe evoked by urushiol an antigenic component of poison
ivy or poison oak, and presents as vesicular dermatitis.
In these reactions, the environmental chemical binds to selfproteins and cause structural modification, which are recognized
by T-cells.
These chemicals may also modify the HLA molecules, making
them appear foreign.
Same mechanism is responsible for most drug reactions.

 Drugs alters self-proteins, including MHC molecules, these

neoantigens are recognized as foreign by T-cells, leading to
production of cytokines and inflammation, manifesting as skin
rashes.
CD8+ T Cell-Mediated Cytotoxicity

Cytotoxic T-lymphocytes (CTL) kill antigen-expressing target cells.

CTLs play a role in elimination of virus-infected cells. Viral
peptides are presented by MHC I, and recognized by the TCR of
CD8 cells.
Principal mechanisms of T cell-mediated killing of targets involve
perforins and granzymes preformed and contained in the
lysosome-like granules of CTLs.
Upon recognition, CTL secrete these complex consisting
perforins, granzymes, and other proteins that enter the target
cells by endocytosis.
Inside the target cell, perforin facilitates the release of granzyme
from the complex. The granzymes together with proteases
cleave and activate caspases including apoptosis.
CTLs also express the Fas ligand which can bind to Fas on target
cells and trigger apoptosis.
CD8 Cells can also produce IFN- which are involved in
inflammatory
reactions,
resembling
delayed
type
hypersensitivity.
Seen in:
Transplant Rejection
Hepatitis
Type 1 Diabetes

AUTOIMMUNE DISORDERS
Immune reaction against self-antigens.
Requirements to be considered in assessing autoimmune dse:
1.) Presence of Immune Reaction specific for self-antigen
2.) Evidence that such reaction is not secondary to tissue
damage but is of primary pathogenic significance.
3.) Absence of another well-defined cause of the disease.
They can be organ-specific or generalized (SLE).
Disorders in which chronic inflammation is prominent, it can be
grouped under immune-mediated inflammatory disease, they
may be autoimmune or the immune response may be directed
against normally harmless microbes.

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IMMUNOLOGIC TOLERANCE
It is the phenomenon of unresponsiveness to an antigen induced
by exposure of lymphocytes to that antigen.
Self-tolerance refers to lack of responsiveness to an individuals
own antigens, underlies the ability to live in harmony with the
cells and tissue.
Loss of self-tolerance is the underlying cause of autoimmune
disorders.
Can be classified into two:
CENTRAL TOLERANCE
Death of the self-reactive T-lymphocyte and B-lymphocytes are
killed or rendered harmless during their maturation in the
generative lymphoid organs (thymus, bone marrow).
Negative Selection or Deletion.
Eliminates self-reactive antigen in the T-cell pool.
The antigens encountered by immature lymphocytes in the
thymus causes death by apoptosis.
AIRE (Autoimmune Regulator) is a protein that stimulates
the expression of peripheral tissue-restricted self-antigens
in the thymus, and is critical in the deletion of T-cells.
AIRE mutation results to autoimmune polyendocrinopathy.
Receptor Editing.
When developing B cells detect self-antigens, they
reactivate the machinery of Antigen receptor gene and
generate a new antigen receptor, not specific for selfantigens.
Central tolerance is not perfect, some self-reactive T and B cells
escape to the peripheral system and can inflict injury to the
tissue unless they are deleted in the peripheral tissues.
PERIPHERAL TOLERANCE
Several mechanisms silence potentially autoreactive T and B cells
in peripheral tissues.
Anergy.
Irreversible or prolonged functional inactivation of
lymphocytes, rendering them deactivated.
Mechanism of T-cell Anergy:
Inhibitory signals from receptors that are homologous
to CD28 but opposite in function, these are CTL4-A
which binds to B7 molecules, and PD-1 which binds to
two widely expressed ligands.
B7 in APC is less favors CTL4-A binding (higher affinity),
favoring inhibition of the cell.
B7 in APC increases during innate immune responses
causing more engagement of the CD28, favoring
activation.
Mechanism of B-Cell Anergy:
When B cells encounter self-antigens, they become non
responsive to subsequent antigenic stimulation and
excluded from the lymphoid follicle
B lymphocytes also express inhibitory receptors that
play a role in limiting their activation and preventing
responses to self-antigen.

 Suppression by regulatory T cells.

A population of cells called regulatory T-cells function to
prevent immune reaction against self-antigens.
These develop mainly in the thymus, but may also develop
in peripheral lymphoid tissues.
They express high levels of CD25, chain of IL-2 receptor,
and transcription factor of the forkhead family FOXP3.
Mutation in FOXP3 causes a systemic immune disease
called IPEX, which stands for:
Immune Dysregulation
Polyendocrinopathy
Enteropathy
X-linked
Polymorphism in CD25 is associated with Multiple Sclerosis.
Deletion by apoptosis.
CD4 that recognize self-antigens may receive signals that
promote their cell death by apoptosis.
Two mechanisms:
Express proapoptotic members of the BCL family, called
BIM, without antiapoptotic members of the family like
BCL-2 and BCL-X.
Another mechanism involved the Fas-Fas ligand system.
The death receptor (Fas/CD95) is structurally
homologous to TNF. Engagement of Fas to Fas ligand
can induce apoptosis.
Mutation in the FAS gene causes autoimmune
lymphoproliferative syndrome (ALPS).
Some antigens are hidden from the immune system, they
are sequestered in tissues that do not communicate with
the blood and lymph such as testis, eyes, and brain which
are called Immune-privileged sites.

Association of Non-MHC Genes:

PTPN22
Encodes for Tyrosine Phosphatase.
Associated with rheumatoid arthritis, Type 1 DM.
High prevalence.

NOD2
Associated with Crohns Disease.
NOD receptors with this variant are ineffective at
sensing gut microbes including commensal bacteria,
resulting in entry of and chronic inflammatory
response.
CD25 genes (IL-2 receptor), and IL-17 receptor -chain
Associated with Multiple Sclerosis
ROLE OF INFECTIONS
May be triggered by infections.

MECHANISM OF AUTOIMMUNITY
Autoimmunity arises from a combination of the inheritance of
susceptibility genes, breakdown of self-tolerance, environmental
triggers, which promote the activation of self-reactive
lymphocytes.
This makes autoimmune disorders multifactorial.
Defective tolerance or regulation.
Abnormal display of self-antigens.
Increased expression and persistence of self antigens.
Display of antigenic epitopes that are not expressed
normally may allow anti self-responses to develop
Inflammation or an initial innate immune response.
A strong stimulus for the subsequent activation of
lymphocytes and the generation of adaptive immune
response.

May upregulate the expression of co-stimulators on APCs. If

these cells are presenting self-antigens, the result may be a
breakdown of anergy and activation of T-cells specific for selfantigens.

ROLE OF SUSCEPTIBILITY GENES

Most autoimmune diseases are complex multigenic disorders.
Association of HLA Alleles:
HLA-B27 Ankylosing Spondylitis
HLWA-BW47 21 hydroxylase deficiency
HLA-A Hereditary Hemochromatosis

Some microbes may express antigens that have the same amino
acid sequences as self-antigens; this may result to activation of
self-reactive lymphocytes, a phenomenon called molecular
mimicry.

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GENERAL FEATURES OF AUTOIMMUNE DISEASES

Autoimmune diseases tend to be chronic, sometimes with
relapses and remissions, and the damage is often progressive.
One reason for the chronicity is that the immune system
contains many intrinsic amplification loops.
In self-directed against self-tissues, same amplification
technique exacerbate and prolong the injury.
Epitope Spreading an immune response against one selfantigen causing tissue damage, releasing other antigens,
and resulting in the activation of lymphocytes by these
newly encountered epitopes.
Clinical and pathologic manifestations of an autoimmune disease
are determined by the nature of the underlying immune
response.
Chronic inflammatory diseases are caused by abnormal and
excessive TH1 and TH17 response; examples are psoriasis,
multiple sclerosis, inflammatory bowel diseases.
CD8+ CRLs contribute to killing of cells such as -cells in
Type 1 diabetes.
Some autoimmune diseases such as rheumatoid arthritis
involve both antibodies and T-cell mediated inflammation.

nuclear fragments such as Sm antigen, ribonucleoprotein,

and SS-A and SS-B reactive antigens.
Nucleolar Pattern refers to the presence of a few discrete
spots, represents antibodies to RNA. This pattern is
reported most often in patients with SLE.
Centromeric Pattern Patients with systemic sclerosis
often contain antibodies for centromeres.

Pattern
Homogenous
or Diffuse
Rim or
Peripheral
Speckled
Nucleolar
Centromeric

Representation or Antibodies to
Chromatin
Histones
Occasionally, double stranded DNA
Double stranded DNA
Some nuclear envelope proteins
Non-DNA nuclear constituents
Antibodies to RNA
Antibodies to centromere
Patients with systemic sclerosis

Antibodies to double-stranded DNA and Smith Antigen are the

virtual diagnostics of SLE.
Considered as the Secondary Antiphospholipid Syndrome.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

SLE is an autoimmune disease involving multiple organs,
characterized by a vast array of autoantibodies, particularly
antinuclear antibodies (ANAs), in which injury is caused mainly
by deposition of immune complexes and binding of antibodies
to various tissues.
The disease may be:
Acute or chronic
Remitting and Relapsing
Often Febrile Illness
Injury to skin, joints, kidney, and serosal membranes.
Predominantly affects women affecting 1 in 700 with 9:1 female
to male ratio during women of child bearing age and
reproductive age group. 1:2 ratio in childhood or age of 65
onwards.
SPECTRUM OF AUTOANTIBODIES IN SLE
The hallmark of SLE is the production of autoantibodies.
Antibodies to the DNA, Histones, non-histone proteins, nucleolar
antigens.
Indirect immunofluorescence is used to detect antinuclear
antibodies, the pattern of the immunofluorescence suggests the
type of antibody present:
Homogenous or Diffuse Pattern usually reflects the
antibodies to chromatin, histones, and occasionally, double
stranded DNA.
Rim or Peripheral Staining Pattern Indicative of
antibodies to double stranded DNA and some nuclear
envelope proteins.
Speckled Pattern presence of uniform or variable-sized
speckles, most commonly observed pattern hence the least
specific. It reflects the presence of antibodies to non-DNA

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ETIOLOGY AND PATHOGENESIS OF SLE

Fundamental defect is a failure of the mechanism to maintain
self-tolerance. Both genetic and environmental factors play a
role in the development of SLE.
GENETIC FACTORS
Contributions form MHC and multiple non-MHC genes.
Genetic predispositions:
20% of clinically unaffected first-degree relatives.
Higher concordance in monozygotic twins.
MHC genes regulate production of particular antibodies.
HLA-DQ locus have been linked to the production of antidouble stranded DNA, Anti-Sm, and anti-phospholipid
antibody.
Some lupus patients have inherited deficiency of the early
complement components such as C2, C4, C1q.
C1q deficiency results to defective phagocytic clearance.
Loci associated with the disease such as encoding for proteins
involved in lymphocyte signaling and interferon response.
IMMUNOLOGIC FACTORS
Failure of self-tolerance in B cells.
Defective elimination of self-reactive B cells.
Defects in peripheral tolerance mechanisms
CD4 Helper T cells for nucleosomal antigens escape tolerance.
Contribute to high-affinity pathogenic autoantibodies.
TLR engagement by nuclear DNA and RNA
May activate B lymphocytes.
B cells specific for nuclear antigens may get second signals
from TLRs and may be activated resulting to increased
production of antinuclear autoantibodies.

 Type 1 interferon.
Nucleic acids engage TLRs on dendritic cells and stimulate
the production of interferons.
The self-nucleic acids mimic their microbial counterparts.
This cytokine may activate dendritic cells and B cells, and
promote TH1 response, all of which may stimulate
production of pathogenic autoantibodies.
BAFF
Member of the TNF Family that promotes survival of B-cells
ENVIRONMENTAL FACTORS
UV Light exposure
Exacerbates the disease.
Irradiation may induce apoptosis and may alter DNA in such
way it becomes immunogenic because of enhanced
recognition by TLRs.
UV light can stimulate keratinocytes to produce IL-1 and
promote inflammation.
Sex Hormone
Drugs
Hydralazine, Procainamide, D-Penicillamine can induce SLElike responses in humans.

Mechanism of Tissue Injury

Systemic lesions are caused by immune complexes or type III
hypersensitivity.
The DNA-anti-DNA complex can be detected in the glomeruli
and small blood vessels.
Low serum complement and immunoglobulins in the glomeruli
support the immune complex nature of the disease.
Autoantibodies specific for RBC, WBC, and platelets promote
their phagocytosis and lysis.
In damaged cells where their nuclei is exposed, ANAs can bind to
them and lose their chromatin pattern, become homogenous
and form LE Bodies or Hematoxylin Bodies.

LE Cells are any phagocytic leuocyte that has engulfed the

denatured nucleus of an injured cell.
May develop venous and arterial thrombosis which may be
associated with recurrent spontaneous miscarriages and focal
cerebral or ocular ischemia, referred to as secondary
antiphospholipid antibody syndrome (APAS).

MORPHOLOGY OF SLE
BLOOD VESSELS
Acute necrotizing vasculitis involving capillaries, small arteries,
and arterioles.
Characterized by fibrinoid deposits in the vessel walls.
In chronic stages, it undergoes fibrous thickening and luminal
narrowing.
KIDNEY
50% of SLE patients have clinically significant renal involvement.
All the different glomerular lesions are result of deposition of
immune complexes.
There currently six patterns of glomerular diseases in SLE.
Class I is the least common, and Class IV is the most common.
CLASS
Class I
Class II
Class III
Class IV
Class V
Class VI

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LUPUS NEPHRITIS
Minimal Mesangial
Mesangial Proliferative
Focal Proliferative
Diffuse Proliferative
Membranous
Advanced Sclerosing

Class I (Minimal Mesangial Lupus Nephritis)

Very uncommon
Characterized by immune complex deposition in the mesangium.
Identified immunofluorescence and electron microscopy, but NO
changes in structure in light microscopy.
Class II (Mesangial Proliferative Lupus Nephritis)
Characterized by mesangial cell proliferation
Accompanied by accumulation of mesangial matrix and granular
mesangial deposits of immunoglobulins and complement.
Without the involvement of the capillaries.
Class III (Focal Lupus Nephritis)
Involvement of fewer than 50% of all the glomeruli.
Lesions may be segmental (affecting only a portion of the
glomerulus), or global (affecting the entire glomerulus).
Exhibits swelling and proliferation of endothelial and mesangial
cells associated with leukocyte accumulation, capillary necrosis,
and hyaline thrombi.
Presents with mild hematuria, proteinuria to acute renal
insufficiency.
Some patients progress to diffuse lupus nephritis.
Class IV (Diffuse Lupus Nephritis)
Most common and severe form of lupus nephritis.
Lesions are similar to class II, but differ in extent.
Half or more than half of the glomeruli are affected.
It can be classified as:
Class IV Segmental (IV-S)
Class IV Global (IV-G)
Cellular crescents produced by epithelial cells fill the bowmans
space.
Subendothelial immune complex deposition may create a
circumferential thickening wall, forming wire loop structures.
Lesions may progress to scarring of the glomerulus.
Hematuria, Proteinuria, Hypertension, with mild to severe renal
insufficiency is common.
Class V (Membranous Lupus Nephritis)
Characterize by diffuse thickening of the capillary walls due to
deposition of sub-epithelial immune complex.
Similar to idiopathic membranous nephropathy.
Accompanied by increased production of basement-membrane
like material.
Accompanied by severe proteinuria (nephrotic syndrome).
May occur with focal or diffuse lupus nephritis.
Class VI (Advanced Sclerosing Lupus Nephritis)
Sclerosis of more than 90% of the glomeruli.
Represents end-stage renal disease.

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SKIN
Characteristic erythema, affects the face along the bridge of the
nose and cheeks known commonly as the Butterfly Rash in 50%
of patients, but it can also be seen on extremities and trunk.
Urticaria, Bullae, Maculopapular lesions, and ulcerations.
Histologically there are areas that show vacuolar degeneration
of the basal layer of the epidermis.
In the dermis, there is variable edema and perivascular
inflammation.
Deposition of immunoglobulin and complement along the
dermoepidermal junction.
These are not diagnostics of SLE; they can also be seen in
scleroderma or dermatomyositis.
JOINTS
Non-erosive Synovitis with little deformity.
CENTRAL NERVOUS SYSTEM (CNS)
Neuropsychiatric symptoms have been ascribe to acute vasculitis
Non-inflammatory occlusions of small vessels are sometimes
noted which may be due to endothelial damage by
autoantibodies.
PERICARDITIS AND SEROSAL CAVITY
May be acute, sub-acute, or chronic inflammation of the serosal
linings membranes.
Acute phase mesothelial surfaces covered with fibrinous
exudates.
Later, they become thickened, opaque, coated with shaggy
fibrous tissue that may lead to partial or total obliteration.
Effusions may be present.
CARDIOVASCULAR SYSTEM
May damage any layer of the heart.
Myocarditis or mononuclear cell infiltration is less common and
may cause resting tachycardia and ECG abnormalities.
Valvular Abnormalities, primarily the Mitral and Aortic valves,
manifest diffuse leaflet thickening, associated with dysfunctions
such as stenosis or regurgitation.
Valvular Endocarditis (Libman-Sacks) more common, nonbacterial verrucous endocarditis form a single or multiple 1-3
mm warty deposits on any heart valve distinctively on the
surface of the leaflets.
SPLEEN
Capsular Thickening
Follicular Hyperplasia
Central Penicillary Arteries show concentric intimal and smooth
muscle cell hyperplasia producing onion-skin lesions.
LUNGS
Pleuritis and Pleural effusions.
Chronic Interstitial Fibrosis
Secondary Pulmonary Hypertension

OTHER ORGANS AND TISSUES

Bone Marrow: LE bodies.
Lymph Nodes: Enlarged with hyperplastic follicles, may also
demonstrate necrotizing lymphadenitis.

CLINICAL FEATURES OF SLE

Typically woman with some features:
Butterfly or malar rash
Fever
Pain but no deformity in one or more peripheral joints
Pleuritic Chest pain
Photosensitivity
You need 4 out of the 11 criteria to be considered to have SLE.
Chronic Discoid Lupus Erythematosus
A disease in which the skin manifestations may mimic SLE but
systemic manifestations are rare.
Characterized by the presence of skin plaques, with edema,
erythema, scaliness, follicular plugging, and skin atrophy.
Disease is usually confined to the skin, face, and scalp.
35% of patient show a positive test for generic ANAs, but
antibodies to double-stranded DNA are absent.

Sub-acute Cutaneous Lupus Erythematosus

Presents with predominant skin involvement and can be
distinguished from discoid LE by several criteria.
Skin rash tends to be widespread, superficial, and non-scarring.
Mild Systemic Symptoms.
Strong association with antibodies to SS-A Ag and HLA-DR3.
Intermediate between SLE and LE localized to the skin.
Drug Induced Lupus Erythematosus
In patients receiving drugs such as:
Hydralazine
Procainamide
Isoniazid
D-Penicillamine
Anti-TNF therapy
The drugs are associated with the development of ANAs but
most patients do not express symptoms of SLE.
Abs for double-stranded DNA are rare, but there is high
frequency of Abs for histones.
Persons with HLA-DR4 gene are at greater risk when taking
hydralazine.
Persons with HLA-DR6 gene are at high risk with procainamide.

Ziry kivio darilaros issa, se z hon suvio perzo vaedar issa

(He is the prince that was promised, and he is the song of fire and ice)

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