Cutaneous tuberculosis can present in several forms based on the route of infection and immune status of the host. Lupus vulgaris is the most common form in adults, presenting as slowly expanding reddish plaques on the head and neck. Scrofuloderma results from contiguous spread from underlying bone or lymph node infection, causing ulcerating nodules. Tuberculosis verrucosa cutis, or warty tuberculosis, occurs through inoculation and presents as painless verrucous plaques. Diagnosis involves biopsy showing granulomatous inflammation with caseation necrosis and occasionally visualizing acid-fast bacilli. Treatment involves anti-tubercular therapy targeting Mycobacterium tuberculosis.

1. CUTANEOUS TUBERCULOSIS
BY : Dr. Daulat ram dhaked

3. Introduction
Mycobacterium tuberculosis
• Term „mycobacterium‟ was given in 1896 to a large
group of bacteria producing mould-like pellicles when
grown on liquid media
• Weakly gram-positive, strongly acid fast, aerobic,
nonspore forming, nonmotile, facultative, intracellular,
curved rods measuring 0.2-0.5 X 2-4 um.
• Cell wall contains mycolic acid-rich, long-chain
glycolipids and phospholipoglycans (mycocides)
• Protect mycobacteria from cell lysosomal attack
• These compounds retain red carbol fuchsin dye after
acid decolorization & are responsible for acid-fast
staining of Mycobacteria.

4. • Typical tubercular lesion is epithelioid granuloma with
central caseation necrosis
• Early tubercles are spherical 0.5- to 3-mm nodules with
3 or 4 cellular zones
1. Central caseation
necrosis,
2. Inner cellular zone of
epithelioid macrophages
and Langhans giant cells
admixed with
lymphocytes,
3. Outer cellular zone of
lymphocytes, plasma
cells, and immature
macrophages, and
4. Rim of fibrosis in healing
lesions.

5. Introduction
CUTANEOUS TUBERCULOSIS
• First description by
• – Laennec in 1826
• – prosector’s wart sustained while performing an autopsy
on a patient with spinal TB
• 1/3rd world’s population infected with Mycobacterium
tuberculosis bacteria
• Incidence is low as compared to pulmonary tuberculosis.
• In India cutaneous manifestations of TB (including
tuberculids) are found in < 0.1% of individuals seen in
dermatology clinics.
• Cutaneous TB- 1.5% of extrapulmonary TB

6. Epidemiology
• Childhood TB
– 5-15% of all cases of TB
– most commonly in 10-14 years of age
• Commonest form
– in adults: Lupus Vulgaris
– in childhood: Scrofuloderma and Lichen scrofulosorum

7. Epidemiology
• 70% developed disease in spite of being vaccinated with
BCG
• Male:female = 1.3:1.
• Most patients show clinical infection within first 3 decades
of life.
• Female preponderance in scrofuloderma
• M. bovis found in 1–1.5%

8. Immunopathology
• Skin biopsy specimens examined with monoclonal antibodies
– intense expression of HLA-DR on keratinocytes
– moderate to high Langerhans cell hyperplasia
– infiltration by CD3+ pan-T cells as well as CD8+ and CD4+
T cells(CD4 > CD8)
• Predominant lymphocyte in dermal granulomas
– activated CD3+ T cell
– expressing MHC class II antigens & interleukin 2 receptor

9. Classification
Route of infection
Clinical type
histology
course
Tuberculosis chancre
Tuberculosis verrucoasa cutis
Lupus vulgaris (occasionally)
Non specific
TB specific
TB specific
Localized
Localized
Localized
Secondary tuberculosis
( endogenous source)
Contiguous spread
Scrofuloderma
TB specific
Localized
Auto-inoculation
Orificial tuberculosis
TB specific
Progressive
Haematogenous tuberculosis
Acute military tuberculosis
Lupus vulgaris
Tuberculous gumma
TB specific
TB specific
TB specific
Generalized
Localized
Localized
Lichen scrofulosorum
Variable
Localized
Papular or papulonecrotic
tuberculid
variable
Scattered
Crops
Generalized
Inoculation tuberculosis
(exogenous source)
Eruptive tuberculosis
(Tuberculids)
Micropapular
Papular
Nodular
variable
Erythma induratum of Bazin

10. Classification
• Not previously exposed
• Multibacillary
 Primary inoculation
– Tuberculosis chancre
TB, scrofuloderma, tuberculosis
– Milliary tuberculosis of the skin
periorificialis, acute military
• Previously sensitized hosts
tuberculosis, gumma
– Lupus vulgaris
• Paucibacillary
– Scrofuloderma
Tuberculosis verrucosa cutis, lupus
vulgaris
– Tuberculosis verrucosa cutis

11. Lupus vulgaris
1808, Robert willan
Founder of british
derma.
Gave term LUPUS
To nodular eruption
on face
1887, William
Tilburg Fox
used term LUPUS
VLGARIS
for skin TB
LUPUS word Origin
? Latin word of wolf
? Greek word lepros

12. Clinical features
•
•
•
•
Lesions usually solitary
> 90% involve head and neck in western countries.
In India, Mostly in lower half of the body
Characteristic lesion plaque, border composed of soft,
reddish-brown papules
• Small, reddish-brown, flat plaque of soft, gelatinous
consistency
• Elevated, infiltrated, brown, discoid with areas of atrophy
• Central healing with scarring while periphery continues to
spread

13. Clinical features
• Morphological variants
– classic plaque or keratotic type (most common)
– hypertrophic
– ulcerative
– atrophic
– Planar
• Miliary lupus
– multiple papules/nodules occur simultaneously in disseminated lupus
– occurs after temporary immunosuppression, such as after viral infections
• Unusual presentations
– sporotrichoid pattern
– site of BCG vaccination
– vicinity of Scrofuloderma

14. Clinical features
• Mucosal lesions
– Nasal, buccal or conjunctival mucosa
– Nasal lesions start as nodules, bleed easily, ulcerate,
leading to cartilage destruction
– Early symptom dry rhinitis
– Can produce stenosis of the larynx and scarring
deformities of the soft palate
• Complications
– Scarring, contractures and tissue destruction
– Squamous cell and basal cell carcinomas

15. Diascopy test:
If lesion is pressed by a
glass slide to diminish
vascular component of
inflammation, individual
nodules appear as yellow
brown spots (apple jelly
color), so nodules are
named “apple jelly
nodules”.

16. Histopathology
• Epidermal atrophy, ulceration, or hyperplasia showing Acanthosis,
Hyperkeratosis, Papillomatosis
• Destruction of cutaneous appendages
• Inflammation more prominent in upper dermis
• Epitheloid cells tuberculoid granulomas
• Giant cells (usually of langhans type) with slight or absent caseation
necrosis within the tubercle
• Infiltrate of lymphocytes may be so prominent that the
granulomatous component obscured
• Margins of ulcers pseudoepitheliomatous hyperplasia
• Without deep biopsy diagnosis may be missed

18. Scrofuloderma
(Tuberculosis colliquativa cutis)
1883, Ernest Besnier wrote about scrofulous gumma
Latin word scrofa means a breeding sow, b/c swine
were supposed to be subject to the complaint

19. Clinical features
• Involvement of skin overlying contiguous tuberculosis
focus usually in lymph gland, bone, joint, lacrymal gland
or duct
• Bluish-red nodule breaks down to form undermined
ulceration with granulating tissue at base
• Scarring and fibrosis of lymph nodes may lead to
lymphoedema and elephantiasis
• Skin of the lymphoedematous area may show lesions of
cutaneous TB, usually lupus vulgaris
• Numerous fistulae may intercommunicate beneath ridges
of a bluish skin

20. Histopathology
• Center of lesion abscess formation or ulceration
• Deeper portions and at periphery
– Diffuse dense mixed cell infiltrate of neutrophils, some
eosinophils, plasma cells, lymphocytes and histiocytes
• Tuberculoid granulomas with caseation necrosis seen in
most cases

21. Warty tuberculosis
Synonyms:
Tuberculosis verrucosa cutis
Anatomist’s warts
Prosector’s warts
Verruca necrogenica

22. Clinical features
•
•
•
•
•
Accidental superinfection
Physicians, pathologists and post-mortem attendants
Autoinoculation with sputum
Lower limbs most common site for warty TB in children
Lymphadenopathy not seen in contrast to Scrofuloderma
and Lupus vulgaris

23. Clinical features
• Small, symptomless, indurated, warty papule with slight
inflammatory areola
• Extends to form verrucous plaque
• Irregular extension at edges leads to serpiginous outline
• Involution of centre forming white atrophic scar
• Firm and purplish, red or brown
• Skin biopsy from least keratotic area and incised deep
enough to include the underlying indurated plaque

24. Histopathology
• Hyperkeratosis and Acanthosis
• Acute inflammatory infiltrate
• Abscess formation in upper dermis or within downward extensions of epidermis
• Mid-dermis tuberculoid granulomas with necrosis

25. Primary inoculation tuberculosis
• Earliest lesions
– 2–4 weeks after inoculation
– brownish papule, nodule, or ulcer with an undermined edge and
granular haemorrhagic base
• Edge firm with adherent crust
• Painless, non-healing ulcer or lesion with localized
lymphadenopathy, especially in child, should arouse suspicion

26. Haematogenous tuberculosis
• Miliary tuberculosis
• Usually affects
– Young children
– Immunosuppressed patients
– Concurrent HIV infection
– Following viral infections
• ill patient develops
– Crops of minute bluish papules, vesicles, pustules
– Erythematous nodules
– Haemorrhagic lesions

27. Haematogenous tuberculosis
• Diagnosis sometimes made by biopsy of skin
lesion showing acid-fast bacilli
• Histopathology papule shows a
microabscess containing Neutrophils, cellular
debris, numerous tubercle bacilli surrounded
by zone of macrophages

28. Orificial tuberculosis
• More common in males with impaired cell mediated immunity
• Most commonly in mouth
• Diagnosis suspected when ulcer does not heal inspite of antibiotic
therapy
• Small oedematous red nodules rapidly break down to form painful,
shallow ulcers with undermined bluish edges and do not heal
spontaneously

29. Orificial tuberculosis
• Associated with granulomatous
swelling of lips and may involve the
tongue
• Pain cardinal feature
• Histopathology ulcer surrounded
by nonspecific inflammatory
infiltrate, tuberculoid granulomas
with pronounced necrosis deep in
dermis

30. Metastatic tuberculous abscess
(Tuberculous gumma)
• Malnourished children, immunosuppressed patients, after local trauma
and in association with underlying lymphoma
• Firm subcutaneous nodule or fluctuant abscess most commonly on
extremities
• May break down to form an undermined ulcer often with sinuses
• Histopathology caseation necrosis with rim of Eisinophils and Giant
cells

31. Unusual forms of cutaneous
tuberculosis
• Suspicion by
– Painless abscess formation
– Indolent ulcers with bluish undermined edges
– Nodular, plaque-like or necrotic lesions that defy easy
classification
• Gangrenous or vegetating forms with underlying lung or
glandular disease
• Tuberculous cellulitis-like lesions reported in diabetic and
on oral corticosteroids

32. Congenital tuberculosis
• Exceedingly rare
• Discrete, erythematous lesions, with central
necrotic dell in infants with febrile systemic
illness

33. Tuberculids
• Darier in 1896
• Hypersensitivity reaction to M. tuberculosis or its products in patient
with significant immunity
• Following criteria must be fulfilled to designate a condition as
tuberculid:
– Skin lesion must show tuberculoid histopathology
– Mycobacterium tuberculosis must not be demonstrated in the
lesion
– Tuberculin test must be strongly positive
– Treatment of underlying TB focus must lead to resolution of skin
lesion

34. Lichen scrofulosorum
•
•
•
•
Hebra in 1868
Second most common pattern of cutaneous TB in children
Systemic focus of TB detected in majority cases
Most commonly involve cervical, mediastinal or hilar
lymph nodes
• Symptomless, 0.5– 3.0 mm, closely grouped lichenoid
papules
• Skin-coloured, but may be yellowish or reddish-brown

35. Lichen scrofulosorum
• Perifollicular and appear in groups or in annular arrangement or
plaques
• Adherent crust or small pustule
• Mainly found on the abdomen, chest and back, and proximal limbs
• Antituberculous therapy, the lesions usually clear within 4–8 weeks
without scarring

36. Histopathology
• Superficial dermal granulomas, usually in
vicinity of hair follicles or sweat ducts
• Granulomas composed of epithelioid cells,
with some Langhans giant cells and narrow
margin of lymphoid cells at periphery
• Caseation necrosis absent

37. Papulonecrotic tuberculid
• Necrotizing papulonodular
lesions of size 2 to 8 mm
• Symmetrical crops
• Preceded by fever and
constitutional symptoms
• Pustulation and crusting in
centre and heal with varioliform
scarring in 4-6 weeks
• Sites of predilection legs, knees,
elbows, hands and feet
• Cases on glans of penis have
been reported

38. Papulonecrotic tuberculid
• Young adults predominantly affected
• Focus of TB can be demonstrated in 38 to
75% of patients
• Transition to and coexistence with lupus
vulgaris described
• Association with erythema induratum

39. Histopathology
• Vascular involvement observed in early lesions
• Leukocytoclastic vasculitis or lymphocytic vasculitis.
• Associated with fibrinoid necrosis and thrombotic occlusion of
individual vessels
• Wedge-shaped area of necrosis with broad base toward epidermis
• As wedge gradually cast off, epithelioid and giant cells gather around
its periphery
• Focal granuloma formation poor
• Follicular necrosis or suppuration may occur

40. Erythema induratum of Bazin
• Main pathology in subcutaneous fat
• Indolent, mildly tender, dull red nodules
ranging in size from 5 to 7.5 cm
• Usually develop on calves
• Four times more common in women
• Mycobacterial DNA can be found in up to
77% of skin biopsy specimens
• Lesions may ulcerate
• Precipitated by cold weather
• Ragged, irregular and shallow ulcers with
bluish edge
• Commonest form of cutaneous
tuberculosis found in Hong Kong

41. Erythema Nodosum
• Erytematous, tender, 2.5 to 5 cm nodules that usually
develop on shins
• May also involve the thighs, buttoks and forearm in severe
cases
• Low grade fever and swelling of ankle joints accompany
the skin lesions in some patients
• The lesions regress spontaneously becoming dull red,
violaceous
• Ulceration and scarring not the features
• Skin biopsy reveals a septal panniculitis with no evidence
of vasculitis

42. Cutaneous tuberculosis in immuno-compromised
• Risk of active tuberculosis in people co-infected with HIV and M.
tuberculosis 3–8% per year and lifetime risk >50%
• Ulceration and discharge from surface of lesion
• Biopsy
– neutrophilic infiltrate which may be admixed with histiocytes
– Epithelioid cells, giant cells and well formed granulomas
uncommon
• AFB seen in large numbers
• Culture usually grows Mycobacterium tuberculosis or NTM
• 66% M. avium complex, 10% M. tuberculosis

43. Laboratory Diagnosis
Nucleic acid probes
Nucleic acid sequencing

44. Tuberculin skin test /
Mantoux test
• ID inj of purified protein derivative (0.1 ml (5TU) PPD)
• Culture filtrate of tubercle bacilli containing over 200 antigens
shared with bacille Calmette–Guérin (BCG) and many NTM
• Positive test
– Clinical or latent tuberculosis infection
– Contact with environmental mycobacteria
• Low sensitivity (false negative reactions)
– Immunosuppressed patients
– Patients with severe illness
– Active tuberculosis
– HIV infection
– Immunosuppressant drugs

45. Mantoux test
• False-positive
– exposure to environmental mycobacteria
– within 1 year of BCG vaccination when administered in infancy
• AIIMS study
– doubtful diagnosis of cutaneous tuberculosis 79
– finally categorized as tuberculosis 39
– non-tuberculosis 16
– final diagnosis could not be reached 24
• Readings
– cases
0 to 40 mm
– non-cases
0 to 30 mm
• sensitivity
• specificity
58.97%
62.50%

46. Interferon-γ assays
• Detect latent tuberculosis infection measuring in vitro IFN-γ release in
response to antigens highly specific for M. tuberculosis
• Not confounded by previous bacille Calmette–Gue´rin vaccination,
conferring higher specificity
 Enzyme-linked immunospot (ELISpot) enumerates IFN-γ secreting T
cells, FDA approved in july 2008,expected to replace TST, Sensitivity87.5%,specificity-86.7%
 Whole-blood ELISA, QuantiFERON-TB Gold measures IFN-γ
concentration in supernatant by enzyme linked immunosorbent assay
(ELISA), Uses antigens ESAT-6,CFP-10 and TB7.7, Sensitivity81%,specificity-99.2%
 Genes on Region of difference 1 (RDI1) of M. tuberculosis genome
(deleted from genome of M.bovis BCG and certain NTM)

47. Demonstration of AFB
• Direct demonstration of organism in tissue
smear or biopsy specimens by staining for
AFB is practically of no value in diagnosis of
skin TB

48. Culture
• L-J medium low rates of 8.8% to 10.7% positivity
• Chennai study (3 solid media and 2 liquid media)
– Total patients 213
– Culture positive in 112 (55%)
– lupus vulgaris 60 of 106 (57%)
– verrucosa cutis 40 of 73 (55%)
– scrofuloderma 12 of 24 (50%)

49. BACTEC system
 Culture
– 4 ml of Middlebrook 7H12 broth medium containing 14 C-labeled
palmitic acid for radiometric detection
 0.5 ml of processed specimen is added to broth.
 Growth is ascertained by liberation of 14CO2 as metabolized by
mycobacteria & detected by BACTEC 460 instrument & reported
in terms of growth index (GI) value.
– growth
• BACTEC
62.8%
• L-J medium
25.7%
• combined
74.3% (26/35)
– mean detection time
• BACTEC
17.3 days
• L-J medium 39.4 days

50. Histopathology
• Epithelioid cell granuloma 60 to 100 %
• Recent series histopathology suggestive of tuberculosis
– Total
175(86%) out of 202
– lupus vulgaris
82%
– tuberculosis verrucosa cutis 90%
– Scrofuloderma
95%
• Caseation necrosis
– Scrofuloderma all cases
– Lupus vulgaris 3 of 108
– Tuberculosis verrucosa cutis none

51. Immunohistochemistry
•
•
•
•
•
•
•
Fifty skin biopsy specimens
– Z-N stain & by culture
all negetive for AFB
– Mycobacterial antigen present 68%
– Scrofuloderma
89%
– Lupus Vulgaris
69%
– Tuberculosis Verrucosa Cutis
47%
Mycobacterial antigen demonstrable in majority of cases of
cutaneous tuberculosis using polyclonal antiserum
• Cross reactivity reported in cases of leprosy and in some
fungal infections

52. Polymerase chain reaction
•
•
•
•
•
Victor et al first described use of PCR in cutaneous TB
confirmation of M. tuberculosis
– PCR 1-3 days
– culture 2-6 weeks
mycobacterial DNA demonstrated in
– all different histopathological variants of cutaneous
tuberculosis
– two of tuberculids (papulonecrotic tuberculid and
erythema induratum)

53. DNA PCR
rRNA PCR

54. RNA PCR
• mRNA contrast to DNA and rRNA
– is rapidly degraded
– t1/2 of 3 minutes
– recently viable organism
• Single-tube, nested, RT-PCR (STN RT-PCR)
• For smear-negative samples (1 to 1,000 bacilli/ml)
– sensitivity of PCR 83%
– sensitivity of culture 75%
– specificity of PCR
100%

55. Treatment

59. GLOBAL TB DRUG PIPELINE

61. Treatment
• WHO(2009) recommendations for cutaneous TB
• HIV-negative individuals (adults as well as children) DOTS
– intensive phase 4 drugs H, R, Z, E x 2 mths
– continuation phase H and R x 4 mths
• Daily dosing (2HRZE/4HR) recommended for all newly diagnosed
• Alternatively
– [2HRZE/4(HR)3]: daily intensive phase followed by 3/wkly
continuation phase
– [2(HRZE)3/4(HR)3]: 3/weekly dosing throughout therapy,
provided every dose directly observed

62. Drug therapy
• HIV positive TB patients
– same duration treatment as HIV-negative TB patients
– Or TB patients living in HIV-prevalent setting should receive
daily treatment, at least during the intensive phase
– continuation phase, optimal dosing daily, 3/weeklydosing
acceptable alternative
• Ethambutol should be used in all pediatric cases, irrespective of age
• If systemic focus is detected, corresponding disease categorization
and recommendations should guide choice of drugs and duration of
therapy

63. DOTS
• DOTS (directly observed treatment, short course) launched by WHO
in 1995
– Cornerstone of global efforts at tuberculosis control
– Category 3 regime under RNTCP abolished
– Only 2 regimes in effect (of 1st line drugs)
– Cat 1 for all new cases and Cat 2 for all retreatment cases
– Cat 1: 2 H3R3Z3E3 + 4 H3R3
– Cat 2: 2 H3R3Z3E3S3+ 1 H3R3Z3E3 + 5 H3R3E3
• Culture and drug susceptibility testing (DST) for all previously
treated TB patients at or before the start of treatment

65. Drug therapy
• DOTS-Plus
– 5 or 6 medications inclusive of injectable drug and
fluoroquinolone x 6 months
– 4 oral drugs x 18 months
• • phase II clinical trial:
– Moxifloxacin increased proportion of sputum cultures
that converted to negative, compared with ethambutol
– Improvement in sterilization provided by moxifloxacin
shortened treatment to 3 or 4 months in murine models
of tuberculosis

66. Treatment response
• Safdarjang study from 1992-1997
• Total children
63
• Adhered to complete treatment 24
(6 months Lupus Vulgaris & 10 months Scrofuloderma)
• Lupus vulgaris regressed markedly within 3 months, while
Scrofuloderma took longer
• Lymph nodes took longer to regress than skin lesions in
Lupus vulgaris
• 1 with widespread Lupus vulgaris who completed therapy
relapsed after 18 months
• patients failed to complete therapy 62%

67. Multidrug-resistant (MDR) tuberculosis
• Defined as resistance to rifampicin and isoniazid with or without
resistance to other antituberculous drugs
• MDRTB found in lupus vulgaris, scrofuloderma, and tuberculosis cutis
• 3.6% of new and 20% previously tuberculosis (TB) patients in world
have MDR-TB
• Chennai study
– Resistance to isoniazid either alone or in combination with other antituberculous drugs 7.2%
– resistance to streptomycin 6.3%
– multidrug resistant 2%
• Line probe assay detect rifampicin and INH resistance M. tuberculosis
• India low prevalence of MDR cases but high tuberculous burden

68. Extremely drug-resistant (XDR) TB
• XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
• 10% of MDR-TB cases are also extensively drug-resistant
(XDR-TB)
• By September 2013, 92 countries had reported at least one
XDR-TB case
• Rifampicin resistance can be routinely detected by
molecular probes on microscopy-positive or culture
positive tissue
• No other drug resistance can be routinely checked without
susceptibility tests

71. Mechanism of drug resistant
• Natural or intrinsic drug resistance
– Hydrophobic cell envelope that serves as a permeability barrier
– Drug efflux systems and drug-modifying enzymes
• Acquired drug resistance (drug resistance among previously
treated patients) –
– Most common type of resistance to first-line drugs (20), can emerge
against any antituberculosis agent during chemotherapy
• Primary drug resistance (drug resistance among new cases) –
– Presence of drug-resistant organisms in a previously untreated person
• Cross-resistance can occur between drugs that are chemically
related and/or have same or similar target within mycobacterial
cell
• Mutations in genes encoding drug targets or drug activating
enzymes are responsible for resistance, and point mutations
and / or deletions have been found for all first-line drugs

72. Identification of resistant drugs
• Radiometric method (BACTEC) for first-line drugs
• Proportion method for first-line drugs using solid media
– Seeding of drug free and drug-containing solid media with equal
Quantities Of two dilutions of a Standardized inoculum
• Inhibition of growth
• Mycobacteria Growth Indicator Tube (MGIT), as developed
by BD Diagnostic, contains a modified 7H9 broth in
conjunction with a fluorescence quenching-based oxygen
sensor
• Detection of metabolic changes
– Viability assays based on use of indicator dyes (Pital and colleagues
used resazurin) as an oxidation-reduction indicator
– Flow cytometry, comparing DNA content and number of
mycobacterial cells after 1 - 3 days in presence or absence of drug

73. • Bacteriophage methods
– Luciferase reporter mycobacteriophage technique has been
shown to be capable of distinguishing drug-resistant from drugsusceptible strains of M. tuberculosis in a 48-h assay
• Multiple methods for detection of mutations
– Assays are based on DNA and RNA amplification method is
used, most PCR
– Hybridization, either with allele-specific nucleic acid probes or
with peptide nucleic acid (PNA) probes in ELISAbased methods
– Most rapid and powerful new method, real-time PCR, uses
hybridization with fluorescence labeled probes
• Oligonucleotide, or DNA, micro-arrays
– Micro-arrays consist of a small solid surface made of glass,
silicon, or other material that serves as a platform for anchoring a
large collection of fragments of DNA (oligonucleotides on DNA
chips, cDNA fragments on DNA arrays)

74. Development of new vaccines
• Several approaches to TB vaccine development have been made:
• 1. ‘Improved’ BCG: e.g. over-expression of protective antigens
(AGs), or reconstitution of deleted genes
• 2. Attenuated Mycobacterium tuberculosis: targeted inactivation
(‘knock-out’) of metabolic or virulence genes
• 3. Adjuvanted Protein Subunit Vaccines (also peptides or DNA
vaccines)
– a. hypothesis driven selection: e.g. secreted AGs
– b. empirical selection: e.g. T/B cell recognition and/or MHC binding, combination
of AGs
• 4. Other approaches: live-vectored AGs, e.g. vaccinia (MVP), adenovirus, Salmonella, etc or non-protein AGs, e.g. γd-TCR or CD1binding molecules; conjugates

75. Immunotherapy
• Administration of exoogenous IFNγ or IL-2 and other agents might
augment host CMI responses, improve or accelerate clearance of
tubercle bacilli
• Immunomodulators such as: corticosteroids, HSP65DNA, TGFß
inhibitors, HE2000, IL-4 inhibitors, intravenous
immunoglobulin, rHuIFNγ, Eternacept therapeutic vaccines, and
other drugs and biologics
• Have potential to shorten treatment, by modulating the host response
and helping the immune system eliminate persistent organisms.
• Strategies studied to date in mouse models have been found to reduce
Th2 inhibitory effect on protective Th1 response, either by inhibiting
IL-4 production, or by downregulating Th2 response.

76. VIT-D & TB
• Niels Ryberg Finsen using a form of "concentrated light radiation
“(Photobiomodulation) which won him a Nobel Prize.
• "Introduced light cure for Lupus
• In 2006, Liu and colleagues proved that Mycobacterium tubercolosis
sensing by Toll-like receptor 2/1 (TLR2/1) complex increases
expression of vitamin D receptors (VDR) and cYP27B1 in monocytes.
• 1,25-dihydroxyvitaminD promotes VDR-mediated trans activation of
antimicrobial peptide defensin-2 and cathelicidin (LL-37) and killing
of intracellular Mycobacterium.
• 4 µg/ml concentrations of vitamin D metabolites have been able in a
reproducible way to protect infected human macrophages and restrict
mycobacterial growth in vitro
• Vit D protects against generation of autoimmunity.
• It Inhibits T-helper (Th) 1 T cells response while conversely enhancing
humoral Th2 cells response

77. Nutrients & TB
• Vit. A, Vit. E and Zinc are thought to have role in immune
regulation
• Adequate levels of ascorbic acid, proline and lysine can
prevent MMP-9 secretion and degradation of collagen
matrix in various systems.
• AIIMS study, published in journal PLOS One, showing
that vitamin C arrests growth of TB bacteria and sends
them into a dormancy

78. THANKS