Overview of leprosy Sara Atkinson

world-wide distribution of leprosy significance of the disease understand some immunology behind the clinical spectrum be aware of some of the existing treatment and immunological tests and their shortcomings potential importance of understanding the M. leprae genome and current genetics

Kaufman MH, MacLennan. Robert the Bruce and leprosy. Proc R Coll Physicians Edinb 2000; 30: 75-80

Leprosy - today affects million people worldwide infection relates to overcrowding and lack of hygiene stigma transmission

New case detection trend during the period by WHO region WHO Region New case detection during the year Africa 39,612 47,006 42,814 Americas 42,830 52,435 41,780 South-East Asia 668, , ,635 E Mediterranean 4,758 3,940 3,133 Western Pacific 7,404 6,190 7,137 Total: 763, , ,499

Leprosy - the infection infectious agent Mycobacteria leprae, acid fast, rod shaped bacillus structure of M. leprae and M. tuberculosis are very similar although disease very different affects skin, peripheral nerves, mucosa of upper respiratory tract, eyes intracellular infection BCG vaccination confers some protection

M. leprae within a skin lesion of lepromatous leprosy patient

Leprosy - the infection only host is the human, except?

Diagnosis clinical signs and symptoms skin lesion with sensory loss, with or without thickened nerves and/or positive skin slit smears

WHO-MDT Treatment Dapsone Rifampicin Clofazimine Multibacillary leprosy Rifampicin: 600 mg once a month Dapsone: 100 mg daily Clofazimine: 300 mg once a month and 50 mg daily duration: 24 months Paucibacillary leprosy Rifampicin: 600 mg once a month Dapsone: 100 mg daily duration: six months

Multi-Drug Therapy MDT cures most patients in 6 months (the more infectious patients within 1 year). Early treatment prevents deformities and disabilities and therefore social stigmatisation avoided. Picture courtesy of WHO

Tuberculoid leprosy Very few skin patches Good T cell immunity Very few bacteria

Lepromatous leprosy Very poor T cell immunity and LOTS of bacteria

Why is there a spectrum of host response to the same bacteria?

TT BT BB BLLL PaucibacillaryRidley Jopling (1966)Multibacillary IL-2/IFNtissue expressionIL-10/IL4 Bacterial index Antibody Cell-mediated immunity Leprosy spectrum

Ig levels across the spectrum EC bacterial index (BI) IgM (crude M.leprae) (80) (19) (20) (57)

Results of an LTT (T cell) assay across the spectrum ΔCPM EC HC T L

how does the host respond to infection?

(2) mycolic acid (3) peptidoglycan cytoplasmic membrane galactan Mycobacterial cell wall (1) surface glycolipid (4) lipoarabinomanan (mannose cap)

NK T CTL IFN  IL-12 Mycobacterial killing IL-2 (autocrine action) IFN  IL12/IL18 MM IL-2

Immunology of M. leprae Resides in macrophages, monocytes and Shwann cells receptor mediated phagocytosis and thereby avoiding oxidative burst PGL-1 binds CR1 and CR4, LAM binds MMR and CD14 vesicle resists fusion with lysosomes to maintain neutral pH M. leprae interfere with intracellular signalling LAM and PGL-1 interfere with Ag processing and presentation mechanisms

Reactions occurs often within the first 6 months of treatment complex clinical manifestations eg. swelling, redness, tenderness of skin lesions, pain and tenderness of nerves sometimes with loss of function, irirtis

Two types of reaction RR and ENL Type1 (RR) Borderline Alteration in CMI prednisolone Type 2 (ENL) Lepromatous Immune complexes Systemic, iritis Prednisolone (or thalidomide)

TT BT BB BL LL CMI Type 1Type 2 Reversal reactions Th1 Th2 down-grading up-grading Reactions- a complication of leprosy

IL-6 Type 1 reversal reaction

why are most people resistant to disease?

Has this women infected her daughter?

Why is it rare for people working with leprosy patients to catch leprosy Dr Thomas Chiang, MALC

Multi-case leprosy families: does this indicate genetic susceptibility or exposure?

Genetic susceptibility to leprosy…. Clustering of cases in families and higher concordance in monozygotic than dizygotic twins Associations of HLA-DR2 alleles with susceptibility to leprosy Major susceptibility locus mapped to chromosome 10p13 using sib pairs and parents from South India (mannose receptor?) Polymorphisms in toll-like receptor 2, and cytokine gene promoters (TNF2, IL-10) also associated with MB or PB leprosy Polymorphisms within the IL-12 receptor β2 gene Siddiqui et al 2001 Nature Genetics 27:439; Fitness et al 2002 Genes Immun 3:441; Ohyama et al 2005 J Clin Path 58:740.

genes pseudogenes M.leprae specific genes lipid metab. respiration information pathways regulatory proteins cell wall Cole S.T. et al Massive gene decay in the leprosy bacillus. Nature Feb 22;409(6823): M. leprae genome.

M. lepraeM. tb. bp coding genes1 604 (49%)3 959 (90%) pseudogenes1 116 (27%)6 Cole S.T. et al Massive gene decay in the leprosy bacillus. Nature Feb 22;409(6823):

Use of genome research Vaccine M. leprae-specific human T-cell epitopes, new drugs in vitro systems

Wharram Percy Village largely deserted since 1517, church in use until 1947 Excavations from 1950 – burials excavated from the graveyard of St Martin’s church G708: Maxillae Set in Yorkshire Wolds Young Child buried in St Martin’s churchyard Possible male of around 10 years old Radiocarbon dating suggests AD Deposits of woven bone upon superior surface of hard palate Thickened & rounded margins of pyriform aperture Resorption of anterior nasal spine Rhino-maxillary changes typical of those encountered in leprosy G.M. Taylor et al Journal of Archaeological Science 33 (2006) 1569e1579

Conclusions complex disease, M. leprae resides in macrophages, monocytes and Shwann cells causing many clinical manifestations MDT treatment generally effective spectrum of disease demonstrates CMI is protective (tuberculoid), Ab not protective (lepromatous) immunological/clinical complications…reactions “upgrading” of CMI can lead to tissue damage host genetic factors need for good diagnostic test no simple diagnostic test for leprosy BCG confers some protection against leprosy