Pathophysiology of the immune system

Defense lines against infection

111
 Pattern recognition
Ligands Function
receptors
Secreted receptor
Antimicrobial peptides
Bacterial membrane Opsonization
(AMP)
Defensins Bacterium lysis
Cathelicidins Chemo attractant
Collectins
Mannose binding lectin Microbial carbohydrate Complement activation
Complement activation,
C-reactive protein Bacterial phospholipids
opsonization
Opsonization, pro- and anti
Surfactant Bacterial wall lipid, viral protein
inflammatory mediators
AMP-s act at the site of injury, their main function to eliminate the invading agent or act as a back-up system
to mobilize the cells of the non-specific defense system. If the AMP system is exhausted inflammation develop

112
 Pattern recognition
Ligands Function
receptors
Membrane-bound receptor
Toll-like receptor (TLR) Pathogen associated molecular Immune cell activation
[10 types TLR, (similar pattern (endotoxins, dsRNS, (NFB activation)
structure to IL-1R)] bacterial proteoglycan) TNF-a, IL-1,6,8
Scavenger receptor Lipids Phagocytosis
Mannose receptor Bacterial carbohydrate Phagocytosis
N-formyl-methionin receptor Bacterial N-formyl-methionin Phagocytosis
Secreted and membrane bound
CD 14 and LPS-binding TLR-4 receptor signalization
LPS (endotoxin)
protein TNF-, IL-1,6,8
Cytosol bound
Immune cell activation
NOD-1, NOD-2* Bacterial proteoglycan
TNF-, IL-1,6,8

*nucleotide binding domain {mutation in Crohns disease}

113
114
 Non-specific defense mechanism

M Cells expressing pattern Cells recruited by Specific defense

i recognition molecules Cytokines resident cells IFN-s, IL-s system
c Resident cells Neutrophil granulocytes T cells
r Myeloid dendritic cell (skin, NK cells B cells
o mucus membrane)
b Macrophages
e Mastocytes
s Antimicrobial proteins Antigen presentation /immune system instruction

Homeostatic regulation the inflammatory process is rather an exception than a rule

115
116
Adaptive immunity
1. Antigen recognition
2. Activation of specific lymphocytes effector and memory
cells
Cell mediated immunity: activation of T lymphocytes (IC
microbes)
CD4+
CD8+ cytotoxic T lymphocytes kill cells with IC microbes
Humoral immunity: activation of B lymphocytes (EC microbes)
3. Elimination of antigen and decline of the response

117
 CD4+ TH0
IL-10, TGF-, self tolerance, immune
Antigen presenting cell
suppression Treg
Block autoimmune diseases TGF-
(IL-2)

TNF-
*

*IL-25, 33

118
 IFN-
IL-4

HLA molecules
CD4+ T helper cells
CD40Ligand

119
 Non-specific defense system Specific defense system
Innate immune system Adaptive immune system
Rapid response: within minutes Slow response: over days to weeks
No antigenic specificity: the same Antigenic specificity: each cell is
molecules and cells respond to a wide programmed genetically to respond to a
range of substances single antigen
Immunological memory: on repeated
No memory, i.e. the response does not
exposure the response is faster, stronger
change after repeated exposure
and qualitatively different
Diversity: ability to recognize and
Preformed or rapidly formed components respond to a vast number of different
antigens
Self/non-self recognition: lack of
response (tolerance) to self-antigens but
response to foreign antigens
120
Functions of the immune system
To avoid reacting to harmless antigens (hypersensitivity/allergy)
To discriminate self from non-self
To recognize self and to maintain tolerance to self (autoimmunity)
To recognize non-self and to react to non-self
(immunodeficiency)
To recognize and respond to altered self (cancer)

121
Hypersensitivity reactions (Coombs and Gell
1963)

Type I IgE Ab Type IV T cell

mediated

Type II Ab to fixed Type III Circulating

tissue antigens immune complexes

122
Common features of hypersensitivity disorders
Cause: endogenous (tissue, auto antigen) or exogenous
antigens can initiate
Inheritance of susceptibility genes (HLA-associated or non HLA
genes)
Imbalance between control and effector mechanisms of the
immune system

123
Type I hypersensitivity (allergy, atopy)
Abnormal immune responses to allergens (small, glycosylated,
and soluble proteins)
Antigen/allergen is processed by macrophages or dendritic cells;
presented with class II molecules to CD4+ T helper cells of the
Th2 subclass (exaggerated Th2 response)
Th2 cells secrete IL-4,5 and 13 stimulate B cells and plasma
cells to secrete IgE antibodies. IgE antibodies attach to mast cells
and basophils FcRI
When exposed again to the same allergen, the allergen binds to
antibodies attached to mast cells and basophils and biphasic
inflammatory response develops
Immediate reaction
Delayed inflammatory reaction
124
 Immediate reaction Late reaction

Secondary mediators

Primary mediators
125
 The inflammatory response depends on the target organ
Skin: flushing, itching, edema, urticaria, hives
Respiratory: bronchospasm, laryngospasm, laryngeal edema
GI: nausea, vomiting, cramping, diarrhea
Cardiovascular: tachycardia, hypotension
Anaphylactic shock = systemic immediate hypersensitivity (see
distributive shock)
Response to allergen that directly enters the blood (e.g.,
hypersensitivity to bee/wasp/hornet stings, penicillin, foods, latex)

126
 Forms of type I hypersensitivity reaction
Local or systemic
Incidence of local forms are growing (10-20%)
Hereditary forms (atopy mediated by IgE antibody)
Hay fever (allergic rhinitis, conjunctivitis), urticaria (hives), atopic
eczema and atopic asthma bronchiale
Non-hereditary forms (non-atopic)
Food allergies: peanuts, nuts, fish, shellfish, dairy products
Cold induced asthma and exercise induced asthma
Synthetics: latex
Stinging insects
Drugs: penicillin

127
Type II hypersensitivity
Mediated by antibodies (IgG or M) against cell surface or
extracellular matrix antigens
Type II hypersensitivity effector mechanisms
1. Opsonization + complement and Fc receptor mediated
phagocytosis
IgG or M attracts complement
Antibody-dependent cellular cytotoxicity (ADCC)
2. Complement and Fc receptor mediated inflammation
3. Antibody-mediated cellular dysfunction
1. Opsonization + complement and Fc receptor mediated
phagocytosis

128
 Opsonization + complement and Fc receptor mediated phagocytosis

A.) IgG or M attracts complement

C3b, C4b bearing cells are phagocyted by macrophages in the
spleen, liver, and bone marrow (macrophages have receptors for
IgG and C3b) IgG coated cells are eliminated similarly
MAC C5-9 membrane attack complex action is possible with thin-
walled bacteria (Neisseria)
Diseases
Incompatible blood transfusion
Erythroblastosis foetalis: Rh hemolytic disease of the newborn: IgG
anti-D antibodies from the mother cross the placenta and attach to D
antigen positive fetal cells
129
 ABO hemolytic disease of the newborn: O mother has anti-A,B IgG
antibodies that cross the placenta and attach to A or B fetal cells
Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia
Drug reactions
B) Antibody-dependent cellular cytotoxicity (ADCC) definite role
is uncertain
A cytotoxic reaction in which the Fc receptor-bearing killer cells
(neutrophils, monocytes, eosinophils, NK cells) recognize antibody-
coated (mostly IgG ) target cells and initiate killing. No complement
fixation is required
Examples:
NK destruction of tumor cells
A special type of ADCC IgE antibodies directed against helminths;
major basic protein (toxic to the parasite)
130
 2. Complement and Fc receptor mediated inflammation
Antibodies deposit in extracellular tissue and bind to Fc receptors
of leukocytes complement activation
C5a (C4a, 3a) neutrophil and monocyte recruitment reactive
species, enzyme release
Diseases
Vasculitis (anti-neutrophil cytoplasmic antibodies ANCA),
Goodpastures syndrome (anti-glomerular and pulmonary capillary
basement membrane antibodies nephritis pulmonary bleeding)
Acute rheumatic fever (cross reacting antibodies with antigens on
certain strains of group A Streptococcus)
131
 3. Antibody mediated cellular dysfunction (autoimmune
diseases) Affects hormones, hormone receptors, blood clotting
and growth factors
1. Inhibitory antibody mediated cellular dysfunction
Myasthenia gravis, insulin resistant DM, atrophic gastritis (with
pernicious anemia, achlorhydria), gonadal deficiency, Addisons
disease, pemphigus vulgaris
Myasthenia gravis: blocking antibody against acetylcholine receptors
of striated muscle
Severe weakness; symptoms may appear in newborns (antibody
crosses placenta)
Anaemia perniciosa
Autoantibodies against intrinsic factor

132
Pemphigus vulgaris:IgG antibodies against desmoglein 1 & 3, a protein associated with desmosomes, that leads
to dyshesion blister formation
133
 2. Stimulatory antibody mediated cellular dysfunction
Wegeners granulomatosis (proteinase-3, anti-neutrophil
cytoplasmic antibody), Basedow-Graves disease (later)

134
Type III hypersensitivity
Deposition of circulating antigen-antibody complexes in target
tissues with subsequent activation of complement (IgG or IgM
classical pathway, IgA alternative pathway) and recruitment of
neutrophils and macrophages, which damage the tissue
Exogenous (foreign protein, bacterium, virus) or endogenous
antigen (circulating or cell/tissue component)
Circulating or in situ immune complexes
Deposition of immune complexes and production of disease
depends upon:
Complex size and solubility
Whether neutrophils and macrophages are able to phagocyte
and clear them from the circulation
135
 Forms of type III hypersensitivity
1. Systemic immune complex disease (diphtheria vaccine from
horse serum Pirquet 1911)
2. Local immune complex disease (Arthus reaction)
1. Pathogenesis of systemic immune complex disease
1. Exposure to antigen leads to formation of antibodies
2. Antigen-antibody immune complexes deposit in tissue
3. Development of inflammation
Complement
C5a migration of leukocytes, monocytes
C3a, C5a vascular permeability
Neutrophils and macrophages through C3b and Fc receptors
generation of pro-inflammatory substances
136
137
 Damage to tissue includes
Post-streptococcal glomerulonephritis (bacterial antigens + anti-
streptococcal antibodies)
Polyarteritis nodosa (hepatitis B surface antigen + anti-surface
antigen antibody)
Systemic lupus erythematosus: antibodies see later

138
 2. Local immune complex disease: Arthus reaction*
Localized type of immune complex disease
Farmers lung is an example of an Arthus reaction in its early
stages. Hypersensitivity to thermophilic actinomycetes associated
with moldy hay. Patients develop an interstitial pneumonitis
Later the disease converts into a granulomatous interstitial
pneumonitis (Type IV. hypersensitivity)
*Arthus reaction is induced by injection of an antigen sc into a previously immunized subject or
antibody to this antigen is given iv. Reaction: local cutaneous vasculitis with tissue necrosis

139
Type IV delayed hypersensitivity
Hypersensitivity reactions / diseases caused by antigen-
activated T cells (CD4+ and CD8+)
1. Delayed type hypersensitivity reaction and diseases caused by
cytokine-mediated inflammation
Antigen: soluble
IFN- produced by Th1 cells induces an inflammatory response
dominated by activated macrophages (contact dermatitis, delayed
type hypersensitivity reaction )
IL-17 secreted by Th17 cells promote chronic allergic inflammation
dominated by neutrophils (chronic asthma bronchiale, chronic
rhinitis)

140
Delayed type hypersensitivity reactions and immune inflammation

Contact hypersensitivity
1. Sensitization: stimulates effector, memory and regulatory CD4+ T cells and CD8+
effector cells (10-14 days)
2. Initiation: rapid expression of proinflammatory cytokines and effector T cells and
monocytes

141
Diseases caused by cytokine-mediated
inflammation in type IV hypersensitivity
Contact
hypersensitivity
Epidermal (at the point of
contact with hapten)
Antigen Cr, Ni, DNCB, TNCB,
Toxicodendron species (eg
urushiol)
APC Langerhans cells
Tuberculin-type Granulomatous
hypesensitivity hypersensitivity
Persist in tissues or IC
Intradermal (soluble)
Microbial: M. leprae, M. tuberculosis,
Microbial: M. leprae, M.
Schistosoma
tuberculosis, L. tropica
Non-microbial: Be, Zr, sarcoidosis,
Non-microbial: Be, Zr
Crohns disease
Macrophages, Langerhans cells

TCR TCR, TCR, TCR,

T cells Th1, Th17 , CTL CD4+:CD8+=2:1 Th1, Th2,Th17

Keratinocytes
IFN-, lymphotoxin-, IL-3, GM-CSF
Cytokine TNF-, IL-1, GM-CSF T cells IFN-, macrophage
Maintenance of granuloma TNF-
production IL-3 IL-10, TGF (anegry to stimulation (TNF, IL-1)
dependent
Th1)
Erythema and local induration Hardening, (skin, lung), granuloma
Mantoux test (PPD from M. Tuberculosis, leprosy, leishmaniasis (Th1)
Clinical form Eczema
tuberculosis is injected Schistosomiasis (Th2)
intradermally) Sarcoidosis, Crohns disease
Development 48-72 hr 48-72 hr 21-28 days
142
 Tuberculin (Mantoux or PPD) test: The test is NOT a vaccine. It
does not protect against TB. This type of skin test can be given
to people who were vaccinated with BCG (bacille Calmette-
Gurin), and the skin-test results used to support or exclude the
diagnosis of TB infection

143
2. Diseases caused by CD8+ cytotoxic T cells
Antigen: cell-associated (e.g. virus)
CTLs kill virally-infected cells regardless of whether the
infection is harmful to the host (viral hepatitis)
CTLs may contribute to tissue injury by CD4+ T cells (T1DM)
CD8+ T cells may initiate myocarditis after coxsackievirus B and
development of further myocardial damage by autoreactive
CTLs with CD4+ T cells and antibodies
T cell mediated (CD8 cytotoxic T cell) cytotoxicity

144
T-cell mediated autoimmune diseases
Disease Target antigen Mechanisms of disease
Th17 and Th1 (?) cytokines mediated
Rheumatoid
Collagen? / citrullinated proteins? inflammation
arthritis
Antibodies & immune-complexes ?
Th1 and Th17 cytokines mediated
inflammation
Multiple sclerosis Myelin basic protein
Myelin destruction by activated
macrophages
Type 1 diabetes Pancreatic islet -cell antigens T cell mediated inflammation
mellitus (insulin, glutamic acid decarboxylase) Destruction of islet cells by CTLs
Th17 and Th1 cytokines mediated
Crohns disease Enteric bacteria or self antigen
inflammation
Autoimmune CTL-meditated myocardial cell killing
Myosin heavy chain protein
myocarditis Th1 cytokines mediated inflammation

145
 Comparison of different types of hypersensitivity
Type-I Type-II Type-III Type-IV
Characteristics
(anaphylactic) (cytotoxic) (immune complex) (delayed type)
Antibody IgE IgG, IgM IgG, IgM None
Soluble,tissues &
Antigen Exogenous Cell surface Soluble
organs
Response time 15-30 minutes minutes-hours 3-8 hr 48-72 hr, 21-28 days
Erythema, edema, Erythema, induration,
Appearance Weal & flare Lysis and necrosis
and necrosis granuloma
Basophils and Antibody and Complement and Monocytes and
Histology
eosinophils complement neutrophils lymphocytes

Transferred with Antibody Antibody Antibody T-cells

Erythroblastosis
Allergic asthma, Tuberculin test, poison
Examples fetalis, Goodpasture SLE, farmer's lung
hay fever ivy, granuloma
syndrome

146
Autoimmunity
Maintenance of selective unresponsiveness to self-antigens
under normal conditions
1. sequestration of self-antigens: brain, anterior chamber of the
eye, testis
2. central & peripheral tolerance/anergy of T and B cells
3. regulatory mechanisms (limitation of potential immune
reaction)
Autoimmunity: immune reactions against self antigens
I. Antibody mediated injury antibodies against self-antigens
II. Cell mediated injury tissue injury by autoreactive T cells

147
 Pathogenesis of autoimmune diseases
Genetic predisposition
HLA-II genes, genetic polymorphisms, single gene defects (eg complement)

Environmental factors *

CD8+ T cell Autoreactive CD4+ T cell Autoreactive B cell

Activated
macrophages
IgG autoantibodies

Cell mediated injury Antibody mediated injury

*viral, bacterial infection, drugs, UV

148
 I. Antibody mediated injury
1. Blocking, inactivating antibodies
Myasthenia gravis, insulin resistant DM, atrophic gastritis (with
pernicious anemia, achlorhydria), gonadal deficiency, Addisons
disease, pemphigus vulgaris
2. Stimulatory antibodies
Wegeners granulomatosis (proteinase-3, anti-neutrophil
cytoplasmic antibody), Basedow-Graves disease
3. Complement activation
Goodpastures syndrome: glomerulonehritis + pulmonary
hemorrhage

149
 4. Opsonization
Autoimmune thrombocytopenic purura, autoimmune hemolytic
anemia
5. Antibody-dependent cellular cytotoxicity
Hashimotos thyroiditis
6. Immune-complex formation
Systemic lupus erythematosus, mixed essential cryoglobulinemia
II. Cell mediated injury
Cytokine production
Rheumatiod arthritis, multiple sclerosis, type 1 DM
Cellular cytotoxicity
Type 1 DM

150
151
 Basedow-Graves disease (Hyperthyroidism)
Autoantibodies produced against the thyroid-stimulating hormone
(TSH) receptor that mimic the action of TSH and stimulate
excessive production of thyroid hormones (T4, T3) but are not
subject to the normal TSH/T4 negative feedback loop.
Antibodies were originally classified into those with stimulatory
properties called thyroid-stimulating immunoglobulin or antibody
(TSI, TSAb) and those with inhibitory properties called TSH-
binding inhibiting immunoglobulin or antibody (TBII, TBIA). Both
of these groups are now referred to as thyrotropin receptor
antibodies (TRAb)

152
 Hyperthyroidism results with the clinical manifestations of
increased appetite with weight loss, tremor, atrial fibrillation, heat
intolerance, muscle weakness, osteoporosis, emotional lability,
diarrhea and menstrual irregularity.
Merseburg triad: goiter, exophthalmia and tachycardia
Autoantibodies also cause infiltrative changes (pretibial
myxedema PTM) and exophthalmia due to T cell-mediated
stimulation of fibroblasts.
PTM has also been reported in patients with Hashimoto thyroiditis,
primary hypothyroidism, and euthyroidism.

153
154
Graves ophthalmopathy

Stellwags sign infrequent and

incomplete blinking of the eye
von Graefes sign lowering of the
upper eyelid is jerky during the
downward rotation of the eye
Mbius sign weakness of
convergence

155
156
Systemic lupus erythematosus (SLE)
Chronic, multi-system disease due to excessive auto-antibody
production widespread tissue destruction
Highest incidence: women (black, hispanic), 20-40 years of age
Complement deficiencies in 10 %: C1q, C2, C3 (defective clearance
of immune complexes)
Anti nuclear (DNA, RNA), ribonucleoprotein, nucleosoma and C1q
antibodies
Signs/symptoms
Facial rash/skin rash triggered by sunlight exposure
Oral/nasopharyngeal ulcers
Fever, arthritis, serositis (pleurisy, pericarditis)
Renal injury/failure
CNS involvement with seizures/psychosis
Peripheral vasculitis/gangrene
Hemolytic anemia
157
158
Rheumatoid arthritis (RA)
Chronic, systemic autoimmune disease yet unknown cause
The immune system predominantly targets the synovium that
covers various joints. Inflammation of the synovium is usually
symmetrical with pain, swelling, and stiffness of the joints.
Onset of RA between the ages of 25-55. Women are 3 times
more likely to develop this than men
The immune-chronic inflammatory reaction is characterized by
expression of cytokines, adhesion molecules, chemokines,
recruitment of lymphoid and inflammatory cells
Rheumatoid factor (RF): IgM antibodies that react with Fc region
of IgG1
Anti-citrullinated protein antibody: early RA diagnosis

159
160
 CD4+ Th1 cell number . The disease is probably caused by
CD4+ Th1 cells reacting with fragments of joints antigens such as
collagen or a heat shock protein bound to HLA-II molecules.
Tregs (normal function: preventing autoimmune diseases)
Cytokines TNF-, IL-1, IL-6

1. Butonnire deformity of thumb

2. Ulnar deviation of metacarpophalangeal joints
3. Swan-neck deformity of fingers
161
Immunodeficiency disorders
Most cases are in children less than 15 years of age (80%
male)
Approximately 50% are B cell disorders; 10% T cell disorders;
20% combined B-cell and T-cell immunodeficiencies and 20% for
NK, phagocytic and complement problems
Primary immunodeficiency disorders
Experiments of mother nature
Approximately 100 primarily single-gene disorders of the immune
system
Secondary immunodeficiency disorders
Far more frequent, than the primary immunodeficiency disorders

162
 Primary immunodeficiency disorders
B and T cell deficiencies
Severe combined immunodeficiency

Autosomal recessive

163
B and T cell deficiencies
I. Severe combined immunodeficiency (SCID)
Heterogeneous group of conditions; Deficiency or defective
maturation of stem cells that produce B and T cells disturbed
B and T cell function
Forms: X-linked (males 3:1) [50-60%] or autosomal recessive
[remaining cases] pattern of inheritance
1. X-linked form: disturbance in the chain, in the signaling units
for interleukins
Defect in T and B cell development
Without IL-7 no survival and proliferation of lymphoid progenitor cells
especially T-cell proliferation
T-cells count is very low; B-cells are normal in number but without T-
cell stimulation (IL-2) no function
No NK cells (IL-15-dependent)
164
 2. Autosomal recessive severe combined immunodeficiency
Deficiency of adenosine deaminase (ADA) accumulation of
adenine which is toxic (dATP) to B and T lymphocytes
Other less common causes: loss of function in several genes needed
for lymphocyte differentiation
Both antibody-mediated and cell-mediated immune responses
are non-functional due to lack of mature B cells and/or T cells
Thymus development arrested at ~ 6-8 weeks gestation.
Little to no antibody production

165
 Recurrent, frequently overwhelming infections. Most die in first
few years of life, usually by one year of age
SCID present with life-threatening infections associated with
protracted diarrhea, vomiting, and pneumonia due to Pneumocystis
jorovecii
Blood must be irradiated prior to transfusion in order to prevent
graft versus host reaction and disseminated cytomegolvirus
infection

166
Therapy:
Bone marrow transplantation
Gene therapy with some initial success.
The correct gene sequence for ADA or chain is inserted into a viral vector.
Acute T-cell leukemia in 20% as a consequence

167
 II. Wiskott-Aldrich syndrome (WAS)
Sex-linked recessive WAS(Protein) is missing
Defect in cell migration, and antigen receptors to link to
cytoskeletal elements
Triad of thrombocytopenia (consumptive loss of platelets),
eczema, recurrent sinopulmonary infections leading to early
death due bleeding problems or recurrent infections
Absence of antibody formation to polysaccharide antigens; due to
cytoskeletal defect in T cells
Defects in cellular immunity develop later
Laboratory signs:
Low IgM, normal IgG, and paradoxically elevated concentrations of
IgA, and IgE
168
 Markedly increased risk for developing malignant lymphomas
Treatment: bone marrow transplantation

169
Congenital B-cell deficiency
Brutons agammaglobulinemia or
X-linked hypogammaglobulinemia
IgA deficiency

170
Congenital B-cell deficiency
I. Brutons agammaglobulinemia or X-linked
hypogammaglobulinemia
Sex-linked recessive disease
Failure of pre-B cells to differentiate into mature B cells (Brutons
tyrosine kinase gene defect)
Maternally derived IgG protects the newborn for only a few
months before affected infants begin to develop sinopulmonary
infections with Streptococcus pneumoniae, Hemophilus
influenzae, and Staphylococcus aureus all require opsonization
(IgG) before phagocytosis. Neutralizing antibodies are required to
eliminate enteroviruses (echo, polio, coxsackie) frequent
enterovirus infection; persistent Giardia lamblia infection (due to
lack of IgA)
171
 Cellular immunity (T cell) is intact, so the above viral, fungal and
parasitic infections are relatively well handled
Affected infants require frequent intravenous infusions of
globulins to maintain an adequate level of immunoglobulins to
combat infections
II. Common variable immune deficiency (CVID)
A common, poorly defined heterogeneous group of diseases of
childhood and adolescence with hypogammaglobulinemia and no
recognizable pattern of inheritance

172
 There is an intrinsic defect in the maturation of B cells into
antibody-producing plasma cells; likely due to defective T cell
signaling (maybe a cytokine or some other cell-cell
communication). Clinically similar to Brutons
Recurrent sinopulmonary or GI viral infections or other GI
syndromes [chronic diarrhea (due to giardiasis), malabsorption
(celiac sprue, lactose intolerance), and pernicious anemia
gastric cancer] secondary to decreased immunoglobulin production
Defective T cell signaling
High frequency of autoimmune diseases
Lymphoid neoplasia B-cell tumors (B-cell growth usually kept in
check by T-cells)
Herpes infection is frequent but any other viral infections can occur
173
 III. IgA deficiency
Very common immune deficiency disorder (1:600)
Familial or acquired condition (after some infection chronic loss
of IgA)
Failure of IgA synthesis: an intrinsic defect in the differentiation of
B cells committed to synthesizing IgA or to a defect in T cells that
prevents B cells from synthesizing IgA (defect appears to be a
failure of heavy-chain gene switching)
Most patients are asymptomatic (monomeric IgM to take the
place of the IgA), but autoimmune diseases are frequent (SLE,
rheumatoid arthritis)

174
 If symptomatic, patients usually have recurrent problems with
sinopulmonary GI infections due to the lack of secretory IgA
protecting the mucous membranes
Increased incidence of diarrhea (Giardia), autoimmune diseases
and upper respiratory and gut associated allergies (IgA can block
processing of allergens)
Both serum and secretory IgA levels are decreased; sometimes
patients have IgG2 and IgG4 subclass deficiencies also
Never give gamma globulin or plasma to these patients!
Plasma with IgA will be recognized as a foreign antigen !
anaphylactic reaction
When a transfusion is needed specially washed red blood cells
can be administered !
175
 T cell immunodeficiencies

Hyper IgM szindrma

176
T-cell immunodeficiencies
I. Hyper IgM syndrome
Defect in isotype switching due to a T-cell defect
Helper T cells have a defect in the surface protein CD40L that
interacts with CD40 on the B cell. This results in an inability of the
B cell to switch from the production of IgM to the other classes of
antibodies
Patients have a high concentration of IgM and normal numbers of
T and B cells; very little IgG, IgA, and IgE
IgD levels are not affected by this disease No isotype switching
to IgD (!)
Proliferation of IgM plasma cells (again uncontrolled by T-cells)
into GI tract may cause extensive infiltration and death

177
 Severe recurrent pyogenic bacterial infections beginning early in
life due to impaired opsonization low IgG
Pnemocystis jorovecii infection
Macrophage and T-cell interaction is needed to kill Pnemocystis
jorovecii. Since the T-cell is deficient, the body cant get rid of this
organism.

178
 II. DiGeorges syndrome
In 90% of patients 22q11 deletion syndrome
Congenital absence of the 3rd and 4th pharyngeal pouches, four
parathyroid glands and the thymus. Defects of face (short
philtrum), ears and heart [truncus arteriosus (cyanosis)].
Tetany secondary to hypocalcemia is the first clinical sign
Severe decrease in T-cell production, function
Defective cellular immunity leading to septicemia, chronic
candidiasis, and Pneumocystis jorovecii pneumonia
Blood transfusions containing immunocompetent donor cells may
result in a graft versus host reaction (need to irradiate the blood
before transfusion-also to destroy donor lymphocytes that may
contain CMV)
179
Treatment: thymus grafts and bone marrow transplants
Spontaneous recovery by 5 yrs (if they survive to that age) - At this age, the thymus would
atrophy and the responsibilities of the thymus are taken over by the peripheral lymph node

180
 III. Ataxia telangiectasia (AT)
Ataxia telangiectasia mutated (ATM) gene (two-hit mutation)
ATM gene is a stress kinase, which is activated after ionizing
radiation and phosphorylates p53. With no ATM, you cant
activate p53 and thus become more prone to cancer
Cerebellar ataxia develops between 2 and 5 years of age
defect in Purkinje cells in cerebellum
Prominent arteriolar telangiectasias around the eyes and on the
skin
Severe sinopulmonary diseases
Prone to lymphoid malignancies

181
 IV. Chromosome instability syndromes (Blooms disease,
Fanconis syndrome, ataxia telangiectasia, Werners syndrome,
xeroderma pigmentosum)
Characterized by an increased susceptibility for chromosomal
mutations due to DNA enzyme repair defects
Increased incidence of lymphomas and leukemias
Patients also have thymic hypoplasia with defects in cellular
immunity (75%)
IgA and IgE immunoglobulin levels are decreased and IgG2
subset deficiency is common
Elevated serum alpha-fetoprotein is a good marker for confirming
the disease
Respiratory tract infections are most common cause of death
182
 Characteristic infections of the primary immunodeficiencies
Primary pathogen Primary site Clinical example
Intracellular, bacteria
T-cells viruses, protozoa, Non-specific SCID, DiGeorge
fungi,
Pneumococcus,
Streptococcus, Lung, skin, CNS IgG, IgM deficiency
B-cells Haemophilus
Enteric bacteria and
GI, nasal, eye IgA deficiency
viruses
Staphylococcal, Lung, skin,
Chronic granulomatous disease
Phagocytes Klebsiella regional lymph
(CGD)
Pseudomonas, node
Neisseria,
Haemophilus, C3, Factors I and H, late C
Complement CNS, lung, skin
Pneumococcus, components
Streptococcus
183
Secondary or acquired immunodeficiency disorders

Predisposing conditions
Premature birth, newborns (transient), puberty, aging
Nutritional deficiency: protein, vitamins (A,C), trace chemicals
(zinc, selenium)
Protein loss: protein loosing enteropathy, intestinal
lymphangiectasia, nephrotic syndrome (immunoglobulin loss in
urine)
Hypercatabolic states: muscular dystrophy
Lymphoproliferative disorders, lymphoreticular malignancies
Iatrogenic: chemotherapy, immunosuppression, radiation,
antilymphocyte antibodies, corticosteroids
Autoimmune diseases
Surgical stress, trauma (prolonged hypoperfusion)
Infections (HIV, fungi, chronic bacterial inflammation [TB, lepra])
184
 Pregnancy
DM, uremia
Splenectomy or abnormal spleen function
Clinical manifesestations
1.Lack of immunoglobulins
Decreased production: severe malnutrition, lymphoproliferative
diseases, (chronic lymphocytic leukemia and multiple myeloma),
infection (malaria, septicemia, trypanosomiasis), drugs (cytotoxic
agents, gold, phenytoin, penicillamine and irradiation),
splenectomy
Increased loss or catabolism: protein-losing enteropathy and
intestinal lymphangiectasia, malabsorption, nephrotic syndrome,
exfoliative dermatitis, burns
185
 2.T-cell deficiency
Drugs: high-dose of corticosteroids, cyclophosphamide,
cyclosporin
Lymphoproliferative disorders: Hodgkins disease and advanced
malignancy
Infections: measles, rubella, infectious mononucleosis, TB,
brucellosis, leprosy; HIV-1 and -2 and secondary syphilis
Protein-calorie malnutrition
Other diseases: pyoderma gangrenosum, advanced rheumatoid
arthritis, sarcoidosis, DM and alcoholism

186
Human immunodeficiency virus (HIV)

HIV-1 (1983) most frequent (groups:

M[ain] (A-K), N ,P [Cameroon], O
[Cameroon and Gabon])

HIV-2 (1986) less virulent (mainly in West

Africa)

187
Viral attachment to CD4+ T cells by Gp 120 and to coreceptors by Gp 41
CD4 receptor is expressed on the surface of helper and regulatory T cells, monocytes, macrophages, and dendritic
cells.

CCR5 is expressed on 15-30% of T cells (memory and
activated CD4) on mucous membranes of the genital and
gastrointestinal tract, macrophages, dendritic cells, and
microglia.(CCR5--32 no binding; mutation affects 1%
of Caucasian population)
Up to 90% of newly transmitted HIV uses this coreceptor
and infect macrophages (M or R5 tropism)
HIV patient bone marrow transplant from CCR5--32
donor HIV DNA-PCR negative
CXCR4 is expressed on nearly all CD4 T cells, as well
as CD8 cells, B cells, neutrophils, and eosinophils.
X4-tropic virus emerges in about 50-60% of infected
individuals 5 years after infection. (T or X4 tropism)
Poor outcome
188
189
190
Human immunodeficiency virus (HIV) infection vs.
acquired immunodeficiency syndrome (AIDS)
HIV damages both the adaptive and innate immune systems
The most prominent defects in cell-mediated immunity
Mechanisms of immunodeficiency caused by HIV
Direct cytopathic effect of HIV: loss of CD4+ T cells
Further mechanisms to damage CD4+ T cells by apoptosis, HIV-
specific CTL-s and ADCC
Functional defects in the immune system
Decreased T-cell response
Weak humoral response
Abnormalities in macrophage and dendritic cell function
Opportunistic infections

191
 Kaposis sarcoma

Pneumocystis jorovecii

Chronic mucocutaneous candidiasis Necrotizing periodontal disease

192
Alteration of the immune system
Manipulating the immune system:
Transplantation
Transfer of tissue, cells or organs from one anatomical site to
another
Tumor immunotherapy
Tumor antigens
Monoclonal antibodies against tumor cells
Development of tumor vaccine

193
Pathophysiological aspects of transplantation
Transplant grafting without immune response
Autograft (skin)
Isograft (identical twins)
Transplant grafting with immune response (immunosuppressive
therapy is necessary)
Allograft (most frequent; between genetically not identical humans)
Xenograft (pig human)
Cause of immune response: presence of transplantation antigens
Major transplantation antigens (6 types): HLA-I: HLA-A,B,C and
HLA-II: HLA-DP,DQ,DR
HLA-I antibody and CD8+ cytotoxic T cell response
HLA-II CD4+ T effector Th cell
Minor transplantation antigens: appr 70 types
194
 Immune response against transplants
Hyperacute rejection
The recipient has antibodies against the tissue at the time of
grafting
Mechanism: activation of the complement and clotting systems
Prevention of rejection: cross matching (recipient does not have
pre-existing antibody to the donor)
Acute rejection
Primary immune response against graft
Mechanism: antibody, cytotoxic CD8 T cell, delayed type
hypersensitivity reaction
Without treatment rejection within 7-20 days
Chronic rejection
Graft rejection after a year due to progressive arterial obliteration

195
Acute rejection. Foreign class I HLA on transplants stimulate strong antibody and
CD8+ Tc responses. The foreign class II HLA stimulates CD4+ T cells, which can help
in the generation of B cells or Tcs against class I HLA or can promote delayed-type
hypersensitivity response within the graft. Foreign class II HLA can also stimulate B
cells, resulting in antibody formation against the class II HLA.

196
 Prevention of rejection
1. Identical donor and recipient blood group, no cross reaction
2. HLA typing
Ideal case: all 6 HLA matching
Optimal case: HLA-DR, HLA-A and B
3. Immunosuppression
Antigen specific immunosuppression (future)
Immunosuppression is not antigen specific (present);
Side effects: infection and later secondary tumor development
Forms of clinical immunosuppression

197
 Forms of clinical immunosuppression
1. Anti mitotic agents (azathiopyrin) not tumor specific, other fast
dividing cells are blocked (bone marrow, GI mucosa)
2. Corticosteroids (prednison): block lymphocyte gene-
transcription, function of monocytes and macrophages, anti-
inflammatory
3. Cyclosporins (tacrolimus, sirolimus): block IL-2 (IL-2 is
instrumental in CD4+ T cell proliferation)
4. Polyclonal anti-lymphocyte (CD3, CD4) globulin: anti-human T
cell antibody from gout or sheep blocks T cell function

198
Oncogenesis
Gain of function
Growth factors
Growth factor receptors (erbA, -B, fims, neu)
Signal transduction proteins (src, abl, ras)
Transcription factors (jun, fos ,myc)

Loss of function
Receptors for inhibitors of proliferation
Cell cycle regulators
Checkpoint control proteins
DNA repair proteins (p53)
Apoptotic proteins (bcl-2)
199
Model of sequential genetic alterations
leading to metastatic colon cancer.
Each of the stages indicated is
morphologically distinct, allowing for the
determination of the sequence of
genetic alterations.

200
 Independence
from growth signals
Insensitivity to
growth inhibitory Unlimited growth
stimuli

Tumor cell

Invasion and Insensitivity

metastasis to apoptosis

Ability to
form vessels
Major features of tumor cells

201
Tumor immunotherapy
1. Monoclonal antibody against tumor cells
Monoclonal antibody
Mechanism:
Antibody and complement mediated tumor cell elimination
(opsonization)
Antibody dependent cellular cytotoxicity (ADCC)
For some current monoclonal antibodies see table
Monoclonal antibody + toxic products: radioactive isotopes (131I),
diphtheria toxin, ricin
Results: not promising

202
Monoclonal antibody Tumor antigen Tumor types

Cetuximab, Panitumumab EGF-R Colorectal

Bevacizumab VEGF Colorectal (metastatic)

Trastuzumab Her-2 Brest cancer

Rituximab, Tositumomab,
CD-20 Non-Hodgkin lymphoma
Ibritumomab tiuxetan
Gemtuzumab ozogamicin CD-33 Acute myeloid leukemia

Alemtuzumab CD-52 B-CLL

203
204
 2. Development of tumor vaccines
Theoretical background: Presence of tumor antigens that can
stimulate the immune system
Tumor antigens inducing antibody response
Oncofetal antigen
Carcinoembryonic antigen (CEA), -fetoprotein (AFP)
Altered self antigen
Tumor suppressor gene mutation (p53 in 50% of tumors)

205
 T-cell antigens
Altered self antigen
Proto-oncogen mutation (K-ras mutation in 10% of tumors), c-myc over
expression in lymphoma, leukemia, HER-2/neu epidermal growth
factor receptor breast cancer (Herceptin)
Products of normally unexpressed genes (MAGE, BAGE, GAGE) of
the placenta and testis in melanoma
Antigens of oncogen viruses
EBNA (Epstein-Barr nuclear antigen) in EBV- associated lymphoma
Human papilloma virus cervix carcinoma
Differentiation antigen (prostate specific antigen)

206
 Escape mechanisms of antigenic tumors
Immunodeficiency in the host
Activation of immune regulatory mechanisms: tolerance,
enhancement, suppression
Expression of class I / tumor peptide in the absence of co
stimulation on tumor cell can induce T cell tolerance/anergy
Production of immune regulatory substances
Hormones; cytokines: tumor cells overproduce immune
suppressants such as TGF (suppresses T cell responses)
Degradation of antibody
Active interference with killer mechanisms (FasL-mediated killing
of CTL)
Antigen modulation, antigen shedding, antigen masking
207
Tumors can activate the
immune response (expression
of foreign antigen with HLA I)

Tumors can suppress the

immune response (activation
of T regulatory cells that
release IL-10 and TGF)

The balance determines

whether the cancer becomes
clinically relevant or not

208
1) Cancer cells
express FAS
ligand
2) Bind to FAS
receptor on T
lymphocytes
leading to
apoptosis

209
 Solutions for tumor vaccine:
Immunization with identified tumor antigens to stimulate responses
against the antigen.
Transfecting tumor cells with genes that will make tumor cells
antigenic induce an immune response against both transfected
and non-transfected tumor cells

210
 Metastasis

Tumor
Inject tumor antigen
as vaccine

Introduce gene
into tumor cells
(transfect)

Stimulate patient's
lymphocytes with
tumor antigen in
vitro and inject
stimulated Transfected cells stimulate
lymphocytes back response to tumor antigens
into patient
Immune response destroys211
non-transfected cells
 Pathophysiology
Electrocardiography
Arrhythmias

Prof. Dr. Gyula Szab, MD, PhD, DSc

Professor and Chairman
Department of Pathophysiology
Arrhythmia / Dysrhythmia
The arrhythmia is referring to all rhythms other than precisely
sinus rhythm (i.e. irregular or faster or slower than normal sinus)
Dysrhythmia (abnormal cardiac rhythm) is more accurate term,
but arrhythmia (absence of cardiac rhythm) is used as
synonymous with dysrhythmia
There are two important aspects of arrhythmias
1. The mechanism that produces arrhythmia
1. Altered automaticity (impulse generation)
2. Problems of impulse conduction
3. Triggered activation
2. The site of origin of arrhythmia

64
Mechanisms of arrhythmias
1. Altered automaticity
Normal automaticity: spontaneous phase 4 depolarization (SA,
AV, His-Purkinje fibers)
In altered automaticity the heart rate dependent on
1.Threshold potential
2. Slope of phase 4 depolarization
3. Resting membrane potential
Forms of abnormal automaticity
Decreased automaticity: sinus bradycardia
Increased automaticity: sinus tachycardia, junctional tachycardia,
rare form of ventricular tachycardia
Increased automaticity is limited by the maximal rate of impulse
formation by the pacemaker cells rarely causes clinically
significant tachyarrhythmia
65
 Threshold potential

Resting membrane potential

Slope of phase 4 depolarization

66
 Increase phase 4 slope Decrease phase 4 slope

Sympathetic stimulus Parasympathetic stimulus

Hyperthermia Hypothermia
Hypokalemia Hyperkalemia
Hypoxia & hypercapnia
Cardiac dilation
Local areas of ischemia or necrosis
increases automaticity of neighboring
cells
Phase 4
spontaneous
depolarization

67
 2. Problems of impulse conduction unidirectional conduction
block
Without re-entry block: when impulse conduction is slow or
does not occur. Blocks can be detected at any site within the
pace making and conducting system and can cause conduction
delay or failure
With re-entry the most common tachyarrhythmia
Uneven conduction can occur anywhere in the heart and can result
in re-entry of an impulse into an area that has been depolarized
and repolarized previously. This circular movement of the electrical
impulse results in a single or multiple premature beat, or
tachyarrhythmia.

68
 Re-entry needs 3 conditions to develop
1. available circuit: branching of myocardial fibers to form a circuit
2. differences in the refractory periods of the different limbs of the
circuit
3. slow conduction in the circuit to allow the circuit to recover its
responsiveness by the time the impulse returns
Re-entrant circuits are always abnormal
Present at birth: supraventricular tachycardias (e.g., re-entry
associated with AV bypass tracts and with dual AV nodal tracts)
Ventricular tachycardias never congenital, fibrosis develops in the
ventricles (myocardial infarction or with cardiomyopathic diseases)

69
Re-entry by partial conduction block

The long cardiac refractory period

prevents re-excitement and
extinguishes the action potential.
Partial conduction block can allow
re-entry of the action potential into
previously stimulated regions.
70
Re-entry by increased path length (circus movement)

Normal pathway

Long pathway Absolute refracterity

Absolute refracterity The circus movement,

showing annihilation of the
impulse in the normal
pathway and continued
propagation of the impulse
on the long pathway

71
 3. Triggered activation
Repolarization is followed by a small afterpotential and if this
becomes large enough to trigger another action potential
Afterdepolarizations are due to inherited abnormalities in the
channels that control the movement of ions across the cell
membrane. Factors that prolong depolarization or delay
repolarization helps the development of afterpotential

72
 Early afterdepolarizations:
transient depolarization occur
during either phase 2 or phase 3
of the action potential, and are
seen most commonly in QT
prolongation and polymorphic
ventricular tachycardia (torsade
de pointes)
Possible causes of early
afterdepolarizations:
Acidosis (as occurs in ischemia)
Quinidine (drugs that prolong
action potential duration)
Slow heart rate (contributing
factor)
Hypokalemia
Late afterdepolarizations occur
shortly after completion of
repolarization, manifest as single
premature beats or ventricular
tachycardia, and are seen most
commonly in digitalis intoxication
and high catecholamine states
Possible causes of late (delayed)
afterdepolarizations (all these
factors raise intracellular [Ca2+])
Cardiac glycoside toxicity
(primary cause)
High concentrations of
catecholamines
Ischemia
Rapid heart rates (contributing
factor)
All in combination
73
K+

Na+

74
The site of origin of arrhythmia
Atrial/junctional/ventricular premature beats/complexes
(extrasystoles) or rhythms
Beats or rhythms that originate in places other than the SA node
The ectopic focus may cause single beats or take over and pace
the heart, dictating its entire rhythm

75
Tachyarrhythmias > 100 beats/min
Supraventricular tachyarrhythmias
Ventricular tachyarrhythmias

Bradyarrhythmias < 60 beats/min

76
Atrial premature complex (APC)
APC results from a premature, ectopic, supraventricular
impulse that originates somewhere in the atria outside of the
sinoatrial (SA) node.
1. The R-R interval is irregular. The premature complex disturbs
the regularity of the underlying rhythm.
2. P wave
The shape of the ectopic premature P wave is different from the
sinus P wave.
The premature P wave is followed by a QRS complex if the
impulse is conducted into the ventricles.
3. The PR interval may be normal, short, prolonged, or absent.
The length of the PR interval depends on the ability of the AV
node to conduct the early impulse to the ventricles.
77
 4. The QRS complex is narrow if conduction in the ventricles is
undisturbed.
5. The APC may occur so early that it distorts the T wave of the
previous QRS complex. An abnormal or notched T wave followed
by an early QRS complex should always arouse the suspicion of
APC.
6. APC is usually under compensated

ES

PreES PostES

2 RR > PreES + PostES under compensated

PreES = coupling time or pre-extrasystolic time
PostES = compensatory pause or post-extrasystolic time 78
 Premature atrial complexes

2 RR 2 RR

Atrial bigeminy

Blocked atrial complexes

79
Junctional premature complex (JPC)
JPC is a premature, ectopic, supraventricular impulse that
originates from the area in and around the AV junction.
1. The R-R interval is irregular. The premature complex disturbs
the regularity of the underlying rhythm.
2. P wave
If the P wave is visible, it occurs either just before or just after the
QRS complex and is usually inverted in the inferior leads (II, III
aVF). Inverted P wave implies that the ectopic impulse from the AV
junction was conducted retrogradely (backward) into the atria
If the premature ectopic P wave precedes the QRS complex the
resulting PR interval is abnormally short (< 0.12 sec)
If the P wave is not visible simultaneous conduction to the atria
and ventricles
3. The QRS complex is narrow as long as intraventricular
conduction is undisturbed.
80
 1 1 2
2 1 1

Supranodal beat Mesonodal beat Infranodal beat

81
 Junctional rhythm

82
Accelerated idionodal (junctional) rhythm
83
Ventricular premature complex (VPC)
VPC is a premature, ectopic impulse that originates somewhere
in the ventricles below the bundle of His.
1. The ectopic QRS complex is earlier than expected
(premature).
2. The R-R interval is irregular. The premature QRS interrupts the
regularity of the underlying rhythm.
3. A P wave is usually not seen preceding the ectopic QRS
complex, but an inverted P wave may be visible immediately after
the ectopic QRS complex if the impulse travels retrogradely to
depolarize the atria. Sometimes a non-conducted sinus P wave
(blocked) will distort the T wave of the ectopic QRS complex.

84
 4. The ectopic QRS complex is wider than the normal QRS
complexes and its morphology is different from the normal beats.
The impulse originates from a focus within the ventricles and
spreads through the muscle to depolarize the ventricles
sequentially. It takes longer than normal to do this, so the
resulting QRS complex is wide and tall.
5. The ST segment and T wave slope in the opposite direction
(discordant) from the ectopic QRS complex. Because
depolarization is abnormal, repolarization is also abnormal. ST &
T changes are secondary

85
 6. A long interval of time observed between the VPC and the next
normally conducted beat is called a compensatory pause. It is
assessed by measuring the distance between the two normally
conducted sinus beats that surround the VPC and comparing it
with the baseline R-R interval.
VES
PreES PostES

2 RR > PreES + PostES under compensated

2 RR = PreES + PostES compensated
2 RR < PreES + PostES over compensated

86
Ventricular ectopic complex (extrasystole) RV trigeminy

87
Ventricular ectopic complexes LV bigeminy
88
Nomenclature of early beats
Regular pattern in the onset of premature complexes
Bigeminy: Every other beat is a premature complex
Trigeminy: Every third beat is a premature complex
Quadrigeminy, etc.: Every fourth beat is a premature complex,
etc.
Couplet: two premature complexes in a row
Triplet: three premature complexes in a row
Ventricular tachycardia: three or more premature ventricular
complexes in a row
Non-sustained tachycardia: spontaneous resolution
Sustained tachycardia: continuous tachycardia, with
symptoms of lightheadedness or syncope
89
 Multifocal premature ventricular complexes (PVCs).

PVCs in bigeminy

PVCs in trigeminy
90
LV couplets

91
Triplets or salvos or non-sustained ventricular tachycardia

92
 Multifocal PVCs

V1
RV

LV

93
Atrial fibrillation, left ventricular bigeminy, ventricular couplet and ventricular tachycardia

LV Couplet

Ventricular
tachycardia

94
V1

Bidirectional ventricular tachycardia (~160-170 beats/min)

AV dissociation Atrial rhythm (~72 beats/min)

95
Causes of ectopic beats or rhythms
Hypoxic myocardium
Chronic pulmonary disease, pulmonary embolus
Ischemic myocardium
Acute MI, expanding MI, angina
Sympathetic stimulation
Nervousness, exercise, congestive heart failure, hyperthyroidism
Drugs & electrolyte imbalances
Antiarrhythmic drugs, hypokalemia, imbalances of calcium and
magnesium
Bradycardia
Slow heart rate predisposes one to arrhythmias
Enlargement of the atria or ventricles producing stretch in
pacemaker cells
96
Differential diagnosis of premature beats

Signs Mechanisms
Identical coupling interval between each premature
Re-entry
beats and the normal beat
Not identical coupling interval between each
Enhanced
premature beats and the normal beat, but identical
automaticity
intervals between consecutive premature beats
None of the above items identical Either

97