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Antibodi dan komplemen
Yusuf Alam Romadhon
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Antibodi
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Proses imunitas adaptif
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Sel B sel Plasma immunoglobulin
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Fungsi antibodi
• Melakukan agregasi / inaktivasi toksin dan virion
• Mengaktifkan sistem komplemen• Opsonisasi untuk mempermudah fagositosis
makrofag/netrofil
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Struktur molekul antibodi
• Bagian molekul yang melekat pada “ciri keasingan musuh” atau antigen 2 fragmen ab (Fab)
• Sedangkan batangnya atau fragmen c (Fc) melekat pada “tatakan” reseptor Fc di permukaan sel-sel fagosit dan melekatnya C1q (unsur komplemen)
• Antara ketiga fragmen ini disambung oleh hinge region yang lentur (fleksibel).
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Struktur skematis molekul antibodi
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Peran antibodi dalam imunitas adaptif
• Nama lainnya immunoglobulin• Adalah protein yang berberat molekul besar• Salah satu perannya adalah sebagai
“pengunci” musuh agar “tembakan” komplemen” dan “pengejaran” sel-sel fagosit tidak salah sasaran.
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Caranya?
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Fab = menempel pada antigen patogenFc = menempel pada efektor
Fab
Fc
Fab
Fc
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Satu sekuele complement
Fc
Fab
Fab
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A
A A
A
BB
C
C
C C
C
C
C
C
C
C
C C
C
C
CC
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C
C
A
A
C
C
A
B
C
B
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Heavy Chain
Light Chain
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Struktur antibodi atau molekul immunoglobulin tersusun atas dua
rantai
Rantai berat = ada di dalamRantai ringan = ada di luar
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Hypervariable region pada variable region
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Dalam berikatan dengan antigen, antibodi ternyata
banyak temannya?
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Molekul lain yang berikatan dengan antigen
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Molekul lain yang berikatan dengan antigen
HLA seri A, B dan C HLA seri D
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Molekul lain yang berikatan dengan antigen
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Molekul lain yang berikatan dengan antigen
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Satu jenis molekul antibodi hanya mengenali “satu ciri keasingan” atau satu jenis antigen. Bisa jadi tubuh bakteri ada bagian flagel atau cambuk, ada bagian tubuhnya sendiri atau somasehingga untuk mengidentifikasi “ciri keasingan” bakteri ini tubuh menciptakan 2 jenis antibodi untuk 2 jenis antigen dari satu sel bakteri ini.
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JADI satu antibodi untuk antigen flagel dan satu antibodi untuk antigen soma.
Ini baru satu bakteri, belum ribuan bakteri, virus dan berbagai macam bakal sel kanker
lainnya.
Inilah yang disebut dengan spesifisitas respons imun adaptif
variasinya sangat luar biasa
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Ciri penting antibodi
Antibodi-antibodi yang spesifik untuk antigennya masing-masing dihasilkan oleh sel plasma, hasil
diferensiasi dari sel B.
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Satu antigen = satu sel T = satu sel B = satu antibodi
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Fab = pembeda Ig satu dengan lain = variable region
Fc = sama antar Ig = constan region
• Dapat dikatakan di daerah fragmen ab itulah yang berbeda antara antibodi yang satu dengan yang lain sesuai antigen yang dia ikat. Karena bervariasi antar antibodi yang satu dengan yang lain regio variabel.
• Tetapi, di luar itu struktur molekulnya sama antara antibodi yang satu dengan yang lain. regio konstan.
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Antibodi-antibodi yang spesifik untuk satu antigen, menyelimuti bakteri yang mengandung
antigen yang dimaksud. Fab melekat pada antigen, sementara Fc-nya merupakan tempat melekatnya permukaan
makrofag atau netrofil yang terdapat reseptor Fc yang jumlahnya banyak.
Karena dipandu perlekatan Fc antibodi dan reseptor Fc, maka makrofag / netrofil tidak salah sasaran dalam melakukan pencaplokan bakteri.
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Variability and diversity of Immunoglobulin
• Bagian fragmen antigen binding (Fab) adalah tempat melekatnya antigen pada antibodi.
• Terdapat 107 – 109 kemungkinan determinan antigen Berarti ada kemungkinan 107 – 109 jenis perbedaan struktur molekul peptida yang berada di fragmen antigen binding ini.
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• Berarti ada kemungkinan 107 – 109 jenis koloni sel B yang akhirnya berubah menjadi sel plasma penghasil antibodi yang sangat spesifik ini.
• Dikatakan koloni karena sel B untuk satu jenis antigen akan menggandakan diri sesuai dengan kebutuhan sebelum akhirnya menyusut jumlahnya menjadi sel B memori, dimana ketika ada paparan antigen yang sama di lain waktu akan menggandakan diri lagi.
Variability and diversity of Immunoglobulin
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Satu antigen = satu sel T = satu sel B = satu antibodi
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Variability and diversity of Immunoglobulin hipermutasi
somatik
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• Untuk itu sel B harus melakukan penyesuaian kode genetik agar bisa mengejar kesesuaian peptida yang dihasilkan dengan antigen yang akan ditangani.
• Keadaan ini berimplikasi ada 107 – 109 variasi DNA kode genetik yang nantinya ditranlasi menjadi RNA dan mRNA, sebagai template / cetakan yang digunakan untuk menghasilkan bagian peptida antibodi di segmen Fab.
• Keadaan ini juga dijumpai pada reseptor sel B dan reseptor sel T yang juga berspesialisasi terhadap variasi yang luas jenis antigen yang harus mereka tangani.
• Variasi yang sangat luas dari DNA ini dikenal dengan nama hipermutasi somatik.
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Satu determinan antigen (epitop) = satu molekul antibodi
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Isotipe / klas Immunoglobulin
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Kelas Rantai H Rantai L Subunits mg/ml Keterangan
IgG Gamma kappa atau lambda
H2L2 6–13 Dapat melintasi plasenta
IgM Mu kappa atau lambda (H2L2)5 0.5–3
Antibodi pertama muncul setelah
imunisasi
IgA Alpha kappa atau lambda
(H2L2)2 0.6–3 Konsentrasi tinggi dalam sekresi
IgD Delta kappa atau lambda H2L2 <0.14 Fungsi tidak diketahui
IgE Epsilon kappa atau lambda
H2L2 <0.0004Terikat pada basofil dan sel mast & sensitisasi
timbulkan reaksi alergi
Ringkasan sifat lima kelas antibodi
"mg/ml" konsentrasi yang normalnya dalam serum manusia
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Respons immunoglobulin pada vaksinasi
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Name Types Description Antibody Complexes
IgA 2
Found in mucosal areas, such as the gut, respiratory tract and urogenital tract, and prevents colonization by pathogens.[10] Also found in saliva, tears, and breast milk.
IgD 1
Functions mainly as an antigen receptor on B cells that have not been exposed to antigens.[11] It has been shown to activate basophils and mast cells to produce antimicrobial factors.[12]
IgE 1Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Also protects against parasitic worms.[6]
IgG 4
In its four forms, provides the majority of antibody-based immunity against invading pathogens.[6] The only antibody capable of crossing the placenta to give passive immunity to fetus.
IgM 1
Expressed on the surface of B cells and in a secreted form with very high avidity. Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG.[6][11]
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Sintesis protein antibodi
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Sintesis antibodi
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Sekedar pengingat • Antibodi merupakan molekul protein, dimana sintesisnya
memerlukan 2 proses besar yaitu • Transcription = DNA → RNA • Translation = RNA → protein• Untuk kepentingan pembentukan protein, DNA yang terletak
dalam kromosom pertama kali dilakukan “penulisan naskah ulang” atau transkripsi dengan kepentingan agar nanti mudah “diterjemahkan”. Transkripsi adalah merubah DNA menjadi tRNA. tRNA ini diubah menjadi mRNA (messenger RNA) agar mudah dibaca oleh ribosom menjadi asam amino. Kumpulan asam amino yang terbentuk menjadi peptida. Dan kumpulan peptida ini disusun menjadi protein.
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Sintesis protein
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Sintesis protein
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Struktur molekul antibodi
Gambar molekul antibodi berikut terlihat bahwa terlihat pada rantai ringan di daerah hipervariabel terdapat 108 asam amino, dan di daerah konstan sebanyak 214 asam amino. Sedangkan pada rantai berat daerah hipervariabel mengandung 118 asam amino dan di daerah konstan terdapat 446 asam amino.
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Satu determinan antigen (epitop) = satu molekul antibodi
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Urutan sintesis protein antibodi
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Urutan sintesis protein antibodi
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Urutan sintesis protein antibodi
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Urutan sintesis protein antibodi
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Urutan sintesis protein antibodi
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Immunoglobulin switching isotype
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Immunoglobulin switching isotype
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Kelas Rantai H Rantai L Subunits mg/ml Keterangan
IgG Gamma kappa atau lambda
H2L2 6–13 Dapat melintasi plasenta
IgM Mu kappa atau lambda (H2L2)5 0.5–3
Antibodi pertama muncul setelah
imunisasi
IgA Alpha kappa atau lambda
(H2L2)2 0.6–3 Konsentrasi tinggi dalam sekresi
IgD Delta kappa atau lambda H2L2 <0.14 Fungsi tidak diketahui
IgE Epsilon kappa atau lambda
H2L2 <0.0004Terikat pada basofil dan sel mast & sensitisasi
timbulkan reaksi alergi
Ringkasan sifat lima kelas antibodi
"mg/ml" konsentrasi yang normalnya dalam serum manusia
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Immunoglobulin switching isotype
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Immunoglobulin switching isotype
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Reseptor sel B dan Ig
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Reseptor sel B dan antibodi
Molekul reseptor sel B masih dalam keadaan melekat di permukaan sel B mulai saat belum matang sampai matang, setelah sel B berdiferensiasi menjadi sel Plasma berubah menjadi antibodi yang lepas terbawa plasma darah.
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Struktur molekul reseptor sel B/Ig dan gen pengkode
• Molekul antibodi dan reseptor sel B terdiri dua rantai yaitu rantai berat (heavy chains) dan rantai ringan (light chain).
• Keduanya menyusun regio konstan dan regio variabel dan disusun dengan menggunakan kode genetik untuk antibodi dengan rincian sebagai berikut:– Gen rantai berat (heavy chain) – terletak pada kromosom
14 dengan panjang basa nitrogen 1250 kb– Gen kappa (κ) rantai ringan (light chain) – terletak pada
kromosom 2 dengan panjang basa nitrogen 1820 kb– Gen lambda (λ) rantai ringan (light chain) – terletak pada
kromosom 22 dengan panjang basa nitrogen 1050 kb
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Over 15,000,000 combinations of variable, diversity and joining gene segments are possible. Imprecise recombination and mutation increase the variability into billions of possible combinations.
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Reseptor sel T dan gen pengkodenya
• Untuk reseptor sel T terdiri dari dua macam reseptor yaitu – Reseptor alfa beta () yang tersusun dari rantai
rantai dan rantai – Reseptor gama delta () yang tersusun dari rantai
dan rantai
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Lanjutan struktur molekul dan gen pengkode
• Rincian gen yang menyusun keempat jenis rantai ini adalah sebagai berikut :– Gen penyusun rantai terletak pada kromosom 7
dengan panjang basa nitrogen 620 kb– Gen penyusun rantai , terletak pada kromosom
14 dengan panjang basa nitrogen 1000 kb– Gen penyusun rantai terletak pada kromosom 7
dengan panjang basa nitrogen 200 kb
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Untuk belajar lebih lanjut tentang bagaimana struktur antibodi dan reseptor sel B dan T
Abul K Abbas & Andrew H Lichtman; Cellular and Molecular Immunology 5th 2005 chapter 7
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Terapi monoklonal antibodi
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Penyakit berkaitan kelainan antibodi
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Penyakit terkait kelainan antibodi
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Sumber alergen terkait IgE
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85% penderita dermatitis atopi IgE
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Penyakit terkait kelainan antibodi (penyakit jantung rematik)
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Penyakit terkait kelainan antibodi (miastenia gravis)
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Penyakit terkait kelainan antibodi (antibodi anti sperma)
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Penyakit terkait kelainan antibodi(Graves disease)
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Penyakit terkait kelainan antibodi(Graves disease)
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Monoclonal Antibodies
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Antibodi monoklonal
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Kegunaan monoklonal antibodi
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Pemeriksaan immunofluorescen
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Cotoh obat yang menggunakan monoclonal antibodi
• Chimeric mAbs are 66% human structure and 34% murine (from the variable region of the original mouse Ab) and include rituximab and basiliximab.
• Fully human mAbs, such as ofatumumab and adalimumab, have a 100% human structure and may be derived from either human cells or genetically engineered mice
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Contoh penerapan monoclonal antibodi
sebagai obat
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Penyakit terkait kelainan antibodi(Graves disease)
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Penyakit terkait kelainan antibodi(Graves disease)
Rituximab
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Pemeriksaan laboratorium antibodi
Pemeriksaan Widal untuk Typhoid fever Salmonella Typhosa, Salmonella Paratyphosa A, B
Titer OTiter H= 0, 1/8, 1/16, 1/32, 1/64 .....
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Komplemen
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Definition
• The complement system is a biochemical cascade that helps, or “complements”, the ability of antibodies to clear pathogens from an organism.
• It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime.
• However, it can be recruited and brought into action by the adaptive immune system.
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Definition continue..
• The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).
• When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages.
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Definition continue...
• The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex.
• Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors.
• These proteins are synthesized mainly in the liver, and they account for about 5% of the globulin fraction of blood serum.
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Functions of the Complement
The basic functions of the complement• Lysis of cells, bacteria and cell infected by viruses.• Opsonization, which promotes phagocytosis of particular
antigens. • Binding to specific complement receptors on the cells of
the immune system, triggering specific cell functions, inflammation, and certain immunoregulatory molecules.
• Immune Clearance, which removes immune complexes from immune system and deposits them in the spleen and liver.
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Function of the complement
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Three biochemical pathways activate the complement system
• Classical complement pathway• Alternative complemen pathway• Mannose-binding lectin pathway
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Biochemical pathway
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Classical pathway
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• The classical pathway is triggered by activation of the C1-complex (C1q, two molecules of C1r, and two molecules of C1s thus forming C1qr2s2), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgGs are needed), or when C1q binds directly to the surface of the pathogen.
• Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r (a serine protease) molecules.
• They then cleave C1s (another serine protease). The C1r2s2 component now splits C4 and then C2, producing C4a,C4b,C2a,and C2b.
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• C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), which promotes cleavage of C3 into C3a and C3b; C3b later joins with C4b2a (the C3 convertase) to make C5 convertase (C4b2a3b complex). The inhibition of C1r and C1s is controlled by C1 inhibitor.
• C3-convertase can be inhibited by Decay accelerating factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.
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The alternative pathway
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The alternative pathway
• Triggered by spontaneous C3 hydrolysis directly due to the breakdown of the thioester bond via condensation reaction (C3 is mildly unstable in aqueous environment) to form C3a and C3b. It does not rely on a pathogen-binding antibodies like the other pathways.
• C3b is then capable of covalently binding to a pathogenic membrane surface if it is near enough. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated by rejoining with each other. Upon binding with a cellular membrane C3b is bound by factor B to form C3bB. This complex in presence of factor D will be cleaved into Ba and Bb. Bb will remain covalently bonded to C3b to form C3bBb which is the alternative pathway C3-convertase. The protein C3 is produced in the liver.
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The alternative pathway continue...• The C3bBb complex, which is "hooked" onto the surface of
the pathogen, will then act like a "chain saw," catalyzing the hydrolysis of C3 in the blood into C3a and C3b, which positively affects the number of C3bBb hooked onto a pathogen.
• After hydrolysis of C3, C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b. C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane, "punches a hole," and initiates cells lysis. C5a and C3a are known to trigger mast cell degranulation.
• IgA is associated with activating the alternative path
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Lectin pathway (MBL - MASP)
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Lectin pathways
• The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL), and ficolins, instead of C1q.
• This pathway is activated by binding mannose-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively),which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway.
• Ficolins are homologous to MBL and function via MASP in a similar way. In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.
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3 kemungkinan hasil kerja komplemen
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Aktivasi komplemen saat sepsis
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Opsonisasi C3b fagositosis makrofag/netrofil
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Efek biologis bagian-bagian komplemen
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Peran komplemen dalam eliminasi sel kanker