TEMAS PRACTICA

INMUNOLOGIA B1P2
INTRODUCCION SESION 2
SISTEMA COMPLEMENTO

Dr. José Luis Suárez Vallejos.

CARDIOLOGIA MEDICINA INTERNA
Hospital Sullana Piura MINSA UCV 2022-1
 CASO CLINICO SESION 2 SISTEMA COMPLEMENTO

FILIACION: Mujer 19 años edad Antecedentes Patológicos o contributorios con Enfermedada Actual de paciente
RELATO Examen físico PA: 110/60 mm Hg, FC 120 latidos/min, FR
26/min y TC 38.8°C; palidez marcada, edema en
Mujer 19 años edad admitida con historia 4 meses de miembros inferiores,IGY++ RHY++, signo de Kussmaul
evolución por edema progresivo de miembros inferiores, presente, ruidos cardiacos alejados; murmullo vesicular
disnea progresiva, ortopnea, y dolor torácico tipo punzada. disminuido en ambas bases pulmonares sin crepitantes
EXAMENES AUXILIARES: Exámenes Auxiliares: Hemoglobina 4.42gr%Hto 13.2% VMC 82.4 HMC 27 Leucocitos: 5410xcel mm3 Segmentados 87%
Linfocitos 9.3%. Proteínas Totales: 5gr% Albumina 1.5gr% Test de Coombs Positivo Examen de orina: Albuminuria y Hematuria
ECG mostró complejos de bajo voltaje, alternancia eléctrica y taquicardia sinusal y rayos X tórax Cardiomegalia global y oligoemia pulmonar (
Figura 1). Ecocardiografía transtorácica Efusión pericárdica masiva; procediéndose a drenaje pericárdico a cielo abierto y biopsia de
pericardio. Se extrajo 1 000 cc de líquido pericárdico color amarillo citrino con características exudativas y adenosina deaminasa (ADA) en 10,5
U/L. La biopsia mostró pericardio engrosado con inflamación crónica linfoplasmocitaria con depósitos de fibrinaCo2 Otros

Radiografía de tórax ECG otros,Ritmo Irregular 60 por minuto BCRIHH Ecocardiografia

Transtoracica
Problemas de Salud
1.-Insuficiencia Cardíaca Congestiva Derrame Pericárdico Taponamiento Cardíaco
Evolución con Síntomas y signos de Inestabilidad Hemodinámica y Trantorno Conducción Cardíaca BAV Intermitente
 2.-Anemia Hemolitica Autoinmune == COMPROMISO HEMATOLOGICO
3.-Síndrome Nefrótico+Nefritico Autoinmune ==COMPROMISO RENAL
4.-Patrón ANA POSITIVO y Disminución del Complemento Sérico C3 == ANA+C3 disminuido. MIOPERICARIDITS LUPICA EN TRATAMIENTO CON CICLOFOSFAMIDA Y
PULSOS DE METILPREDNISOLONA, LUEGO CN PREDINISONA Y MESNA.
 
DISCUSIÓN
Miocarditis lúpica forma parte del compromiso miocárdico, puede tener una evolución benigna o tórpida hacia la
miocardiopatía dilatada. En nuestra paciente el compromiso se extendió a pericardio (taponamiento pericárdico) y
posteriormente a miocardio (disfunción sistólica).
Pericardio se compromete por cambios agudos o crónicos con depósito granular de inmunoglobulinas y complemento C3.
También se demuestran complejos inmunes granulares finos y depósitos de complemento en las paredes y tejido
perivascular de los vasos sanguíneos miocárdicos.
Miocarditis aguda, manifestación poco común con frecuencia de 8 a 25%.
Insuficiencia cardiaca izquierda aguda en pacientes con LES, puede ser causada por eventos infecciosos, isquémicos, por
auto anticuerpos antifosfolipídicos, miocarditis autoinmune, vasculitis de vasos pequeños, o medicación como por
ejemplo esteroides o antimaláricos.
Hipokinesia global puede ser hallazgo ecocardiográfico y está presente en aproximadamente 6% de pacientes con LES.
Miocarditis lúpica puede ser diagnosticada en base a sospecha clínica y evidencia ecocardiográfica de una fracción de
eyección reducida además de anormalidades en la motilidad global y segmentaria, luego se evidenciaron trastornos de
conducción, disfunción, y elevación de enzimas cardiacas. Marcadores inmunológicos positivos para LES, con lo que se
concluyó en miopericarditis lúpica, iniciándose terapia inmunosupresora, teniendo una evolución favorable.
Evolución favorable y dada de alta UCI después 15 días, con ritmo sinusal con extrasístoles supraventriculares aisladas
(estudio Holter) y FEVI 50%, por ecocardiográfico
Complement

What is “it”? A series of serum

proteins.

How is it recognized? By its ability to mediate

cell lysis. (Review the
fascinating story of its
discovery!)

What does it have to do with IMMUNOLOGY?

The overview….

• Complement has • Complement functions

three functions: in two (three?) systems:

– Opsonin – Alternative

– Chemoattractant – Classical

– Lectin-based
– Membrane Attack
Complex (MAC)
The alternative system
• C3 is the principal protein of
concern.

– Exists in high concentrations (1.2

mg ml-1

– Contains an unstable internal

thiolester with slow “spontaneous”
(or serum protease mediated)
cleavage.

• By convention, the smaller product is

designated “a” and the larger “b”
(though there is one exception.)

C3b can bind to bacteria and

enhance phagocytosis.
C3b can bind to bacteria and enhance phagocytosis.
The alternative system
The production of C3b can be catalyzed by “C3 convertase.”

C3 convertase is produced
by C3b associating with
factor B in the presence
of Mg++ to form C3bB
which in the presence
of factor D is cleaved to
C3[bBb].

{Here brackets
substitute for a
horizontal bar above
the letters bBb; by
convention, the bar
over the letters means
that the complex has
enzymatic activity.}
Nota bene: C3[bBb] is C3 convertase.
The alternative system
The production of C3b can be catalyzed by “C3 convertase.”

Because C3 convertase both creates

and contains C3b, the complex
mediates a “positive feedback”
system.

Thus, the reaction has the potential

“to run away” or “explode.”

Factor H can displace factor B. The

C3bH complex is the substrate of factor I which
inactivates C3b by cleaving it into C3d and C3g.

C3[bBb] is C3 convertase.
The alternative system

• C3b has FOUR fates:

(i) it can bind to a microbial surface;

(ii) it can associate with factor B;
(iii) it can associate with factor H; or
(iv) it can bind another C3b.
(What happens here?)

The half-life of C3b is approximately 100

microseconds (so the “choices” occur quickly!).
The alternative system
If C3[bBb] binds a
second C3b, it
becomes
C3[bBb]3b
which is “C5
convertase”.
C5 convertase cleaves C5 into
C5a and C5b.
C5b is unstable and is stabilized
by C6.
C5b6 allows C6 and C7 to
associate and penetrate a
membrane.
The C5b67 recruits C8 which
organizes C9 to form a
“membrane attack complex”
(MAC).
The alternative system

C5 convertase cleaves C5 into C5a and C5b.

C5b is unstable and is stabilized by C6.
C5b6 allows C6 and C7 to associate and penetrate a
membrane.
The C5b67 recruits C8 which organizes C9 to form a
“membrane attack complex” (MAC).
 The alternative system

• Finally….

– C3a and C5a are

– CHEMOATTRACTANTS!

Think of the multiple dimensions of this system which,

incredibly, is the product of evolution. A great puzzle is how
such interdependent systems can emerge incrementally.
The CLASSICAL pathway
Stimulated by antibodies:
specifically: IgM and IgG
(subclasses 1, 2, 3)

Start with C1q a HUGE

protein (410,000 daltons!)

Composed of 18 peptides.

Peptides can associate to

form trimers; six sets of
trimers make C1q.

C1q has helical “stalks” and

globular “heads.”

(N. B. the heads are the

carboxy end and the stalks
are the amino ends)
 The CLASSICAL pathway

Also associated
with C1 are C1r
and C1s which
associate to
make dimeric
pairs (C1r2s2);
the dimeric pair
joins C1q to form
C1qr2s2.
The CLASSICAL pathway
• C1qr2s2 binds to TWO immunoglobulins.

– The complement binding sites of circulating IgM

are too far apart to bind complement;

– only when IgM is bound does it fold so that

C1qr2s2 can “see” nearby complement binding
domains.

– IgG concentrations must be high in the vicinity of

antigens for threshold levels of complement
binding domains to be present.
The CLASSICAL pathway
When C1qr2s2 is bound to requisite number of immunoglobulins, C1r
“autocatalytically” converts to C1[r].

C1[r], in turn, converts C1s to C1[s].

C1[s] cleaves C2 and C4.

C4 is cleaved to C4a and C4b; C4b associates with its “target” which is C2.

C2 is cleaved by C1[s] making C[4b2a] which is a C3 convertase! (Note that 2

is bigger than 2b, this nomenclature being the one exception to the convention that “a” is smaller than “b.”

As with the other C3 convertase, C3b can join C[4b2a] to make C[4b2a]3b
which is also a C5 convertase.
The CLASSICAL pathway
The CLASSICAL pathway
The CLASSICAL pathway
The complement pathways…
The LECTIN pathway
Lectins are proteins which bind to carbohydrates.

Many bacteria have many mannose residues on

their surface. The lectin-based complement
system begins with a “mannose-binding protein”
(MBP).

MBP reacts, in turn, with a MBP-associated

serine protease (MASP).

MASP functions, in effect, like activated C1q[r2s2],

that is a C3 convertase.
The most
amazing
circumstance

Erythrocytes (!)
deliver the
complex of
antigen –
antibody –
complement
to the liver and
spleen for
consumption
by phagocytes.