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🍋Mycobacterium tuberculosis🍎 (Pathogenesis Immunity (prevents fusion…
🍋Mycobacterium tuberculosis🍎
Pathogenesis
Immunity
intracellular pathogen(胞內)
lifelong infection
穿過alveoli
phagocytized by alveolar macrophages
enters the respiratory airways and infec-tious particles penetrate to the alveoli
prevents fusion
藉由blocking the specific bridging molecule
(early endosomal autoantigen 1 [EEA1])
可獲得nutrient和replication
fuse with other intracellular vesicles, permitting access to nutrients and facilitating intravacuole replica-tion.
of the phagosome with lysosomes
phagocytized bacteria
躲避macrophage
nitric oxide
superoxide anions
藉由
catalytically catabolizing the oxidants
感染後
macrophage分泌
interleukin-12 (IL-12)
TNF-α
產生nitric oxide
reactive nitrogen intermediates
intracellular killing
cytokines increase localized inflammation with the recruitment of T cells and natural killer (NK) cells into the area of the infected macrophage
T 細胞
變成TH1 cells (T-helper cells)
IFN-γ
leading to increased phagosome-lysosome fusion
intracellular killing
TNF-α
stimulates production of nitric oxide and related reactive nitrogen intermediates
enhanced intracellular killing
若缺少以上這些東東則增加risk
defects in the receptors for these cytokines, are at increased risk for severe mycobacterial infection
為了有效清除細菌,防止擴散
granuloma
Alveolar macrophages+ epithelioid cells+ Langhans giant cells (fused epithelioid cells)
周圍有dense wall of macrophages and CD4, CD8, and NK T cells
若太多細菌則會形成necrotic or caseous granulomas become encapsulated with fibrin
所以old age or immunosuppressive disease會發病
intracellular mycobacteria form the central core of a necrotic mass
If a small antigenic burden is present at the time the macrophages are stimulated,
the granuloma is small and the bacteria are destroyed with minimal tissue damage
if many bacteria are present,
the large necrotic or caseous granulomas become encapsulated with fibrin that effectively pro-tects the bacteria from macrophage killing
/
The bacteria can remain dormant in this stage
or can be reactivated years later when the patient’s immunologic responsive-ness wanes as the result of old age or immunosuppressive disease or therapy
Epidemiology
humans are the only natural reservoir.
The disease is spread by close
person-to-person contact through the inhalation
of infec-tious aerosols
Large particles are trapped on mucosal surfaces and removed by the ciliary action of the respiratory tree
However,
small particles containing one to three tubercle bacilli can reach the alveolar spaces and establish infection
homeless persons, drug and alcohol abusers, prisoners,
and people infected with the human immunodeficiency virus (HIV)
Clinical Diseases
身體每個部位都有可能發生，但大部分都在肺部
初次：nonspecific complaints of malaise, weight loss, cough, and night sweats
Sputum may be scant or bloody and purulent
：tissue destruction (e.g.,
cavitary disease
)
Extrapulmonary：hematogenous spread
of the bacilli during the initial phase of multiplication.
Diagnosis
radiographic
上肺葉的頂節/後節• 下肺葉的上節
單獨上肺葉前節的侵 犯是相當少見的
肺泡實質化病變
開洞病灶、開洞的結節
粟粒性病變型態• 纖維結節樣變化
結節(結核瘤)
肋膜積液
鈣化的結核瘤– 原發病灶
positive skin test
PPD
結核菌素是萃取自結核菌的蛋白質。目前廣為各國所使用的結核菌素有PPD-S、及PPD RT23兩種
自民國90年9月1日起，台灣採用PPD RT23 2TU
用右手食指輕摸反應硬結（induration）之邊緣，以公厘（mm）尺測量其橫徑（即與前臂長徑垂直方向之長度）
未接種卡介苗者反應≧10 mm者為陽性，＜10 mm者為陰性
已接種卡介苗者反應≧18 mm者為陽性，＜18 mm者為陰性
反應為陽性者應再次詳細查看疤痕或對照黃卡紀錄，以確定是否真正為無疤
卡介苗是由牛型的結核菌經繼代培養減毒後所做成的疫苗，在沒有接種過卡介苗的人，如果T.T.是陽性，則表示曾受到結核菌的感染
但接種過卡介苗的人，在疫苗的保護期內，做T.T.時則會呈現陽性反應。所以接種過卡介苗的人，無法以T.T.來分辨病人是否曾受到結核菌的感染
除非呈現強陽性反應（硬結直徑18毫米以上），或有陽轉（本來陰性變成陽性）時，才表示很有可能受到結核菌的再感染
microscopy/cultures
可是很慢
痰塗片陰性肺結核
至少兩套痰液鏡檢塗片耐酸性染色為陰性(其中包含一套清晨剛起床的痰液)
臺灣目前規範為三套痰液耐酸染色之鏡檢為陰性
痰塗片可偵測出痰中細菌量大的病人
至於痰中細菌量小的病患，即痰塗片陰性者，可藉由痰培養發現細菌
丙型干擾素釋放試
IGRA
IGRA是一種用來診斷是否感染結核菌的抽血檢查，
偵測血液中T細胞對於結核菌抗原的免疫反應
定量T細胞釋出的丙型干擾素做為判讀標準，相較於TST，靈敏度較高
適合用於接受卡介苗多次接種的接觸者或免疫不全的病患
PCR
結核菌的菌體結構複雜，富脂質，疏水性，使得生長的速度緩慢，尤其是肺結核桿菌(Mycobacterium tuberculosis)，每隔十二～二十四小時才分裂一次
所以，利用培養方法來偵測結核菌的存在，往往需要三～八週的時間才可以得到結果，經常延誤治療的時機
PCR技術應用於結核菌感染的快速診斷的原理是利用
特殊設計的引子(Primer)
，針對結核菌某一特定的基因，經過連鎖反應後，得到PCR產物
大都使用本菌的IS 6110基因當作PCR方法的標靶物
所得到的PCR產物再利用呈色法或者免疫雜交反應來確認
萃取結核菌的基因体DNA。實驗的進行，要在密閉乾淨環境下操作，避免遭受外界的污染
PCR技術是非常靈敏的方法，只要臨床檢體存在十～二十個結核菌株，就可偵測到它的存在
缺點：常因受到所使用的引子的限制，每次只能判斷病人的臨床檢體中，是否存在著某一種特定的結核菌而已
Acid fast stain
抗酸性染色的原理是利用分枝桿菌的
細胞璧富含脂質，因此能抵抗鹽酸酒精的脫色，而染上紅色的外觀
然而一般的細菌則會被脫色，呈現與背景相同的色彩(藍綠色)
少數非分枝桿菌類的細菌如奴卡氏菌 (Nocardia)，也會出現弱陽性反應，其外觀極似分枝桿菌，顯微鏡觀察時容易混淆
因此需進一步以抗酸性菌培養 (Acid-Fast culture) 或分子生物的方法 (PCR) 做進一步確認是否為結核分枝桿菌
Mycobacterium
簡介
0.2 to 0.6 × 1 to 10 μm in size
很多lipids：hydrophobic
resistant to many disinfectants and common laboratory stains
不能被decolorized with acid solutions：所以又叫做
acid-fast bacteria(抗酸菌)
‧細胞壁富於脂質而會妨礙色素的通過，因而不 易染色， 一旦染色，不易被強酸脫色，故又稱 耐酸菌(acid-fast bacilli)。
屬於好氣菌
，發育最宜溫度為37°C，最宜酸鹼度pH為6.4~7.0
結核菌的
分裂速度很慢，大約每20小時分裂一次
significant morbidity and mortality
超過150 species
nonmotile, non–spore-forming, aerobic rods
form branched filaments
Physiology
structure
分類依據
(1) their acid-fastness
(2) the presence of
mycolic acids containing 70 to 90 carbons
(3) a high (61% to 71 mol%) guanine plus cytosine (G+C) contentin their DNA
Runyon classification：依照rate of growth和pigmentation
1.nontuberculous mycobacteria (NTM)
2.TB：either nonpigmented or a light tan color
結構
lipid-rich cell wall
特性：acidfastness; slow growth; resistance to detergents, common antibacterial antibiotics, and the host immune response; antigenicity
結核菌對外界抵抗力甚強，在陰暗處結核菌可生存2~3 個月不死。
G(+)
cell wall structure is far more complex
plasma membrane proteins
1.phosphatidylinositol mannosides
2.lipoarabinomannan (LAM)：O-antigenic lipopolysaccharides
3.Additional lipids, glycolipids, and peptidoglycolipids are also present
4.Transport proteins and porins are interspersed throughout the cell wall layers, and these constitute 15% of the cell wall weight
以上拿來purify製成purified protein derivatives [PPDs]：skin test reagents，測是否接觸TB
Mecolic acid:waxy cell wall