Lecture7 - Sex differences in disease Sex differences in...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Sex differences in disease Sex differences in brain diseases female bias male Dr. Arnold February 25, 2011 What factors cause sex differences? if women get depressed but depression is severe major disorder but then men are protected by a f actor against depression we can fi nd what men have and give it to the women to aleviate depression Multiple sclerosis Depression Tourette’s X Neural Tube Defects ADHD Parkinson’s X X X X X Sex differences in disease Female bias autoimmune diseases multiple sclerosis (2-3 X) diabetes rheumatoid arthritis lupus (systemic lupus erythematosus) (9X) depression (3X) osteoporosis (4X) sexually transmitted diseases (2X) anterior neural tube defects migraine Sex differences in disease Male bias ADHD (Attention deficit hyperactivity disorder) Tourette’s Syndrome Parkinson’s Disease mental retardation Fragile X Syndrome autism Duchenne Muscular Dystrophy (1:4000 males) I. Some sex differences in genetic disease are the result of X-linked mutations •  Mutation of X gene means that the protein encoded by the gene is absent or functions improperly (LOSS of function or GAIN of abnormal protein) •  Males lose the only X gene they have at that locus. •  Females with mutation have another X allele that functions normally. Characteristics of X-linked genes XX XY XY Mutant cell Normal cell Heterozygous mutant females are mosaic for mutant and normal cells because of X-inactivation. Males with mutation lack a functional gene entirely. +where do these sex diff come from...gene disorders, mutation of the dna can destroy the gene or misread the protien and would not have the protien work properly. +the mutation sometimes changes the protien and a new f unction emerges which does stuff that it didnt originally do and cause a genetic disease f emale are mosaics of diff x alleles in the functional x chrmosome are shut down and the mutant chromosome are f unctional 1 Carrier Mom* Dad Mom Dad* Arnold Y Chromosome XX 1880 1900 dad mutation XY XX XY dad mom XX XY mom XX XY XX 1936 1967 2002 2004 X-linked inheritance XY XX XY Some X-linked diseases with male bias Male bias X-linked mental retardation Fragile X Syndrome (mental retardation) Duchenne Muscular Dystrophy (1:4000 males) red-green color blindness special case: Rett syndrome found almost only in females because the mutation is lethal to males if you look at it through a micro then it looks broken-fragile x---mothers are the usual character, the girls are s lightly mutated the boys are worse photo pigment x linked gene--red-grene color rett---going backwards in development, happens in girls, if t he boy has it he is never born, lethal gene, Duchenne Muscular Dystrophy Muscles start strong and get weaker with age Males only, female carriers some symptoms Debilitating and eventually death age 15-20 Diagnosis age 4-8 Loss of strength, loss of ability to walk (age 9-14) Failure of diaphragm, inability to breathe mutation of X-linked gene Blood clotting disorders Hemophilia: Clotting disorder As many as 20 different proteins contribute to clotting. Immediately after blood vessel ruptures, platelets, blood proteins react and form a clot. One of the clotting factors is X-linked. Symptoms include: Excessive bleeding Excessive bruising Easy bleeding Nose bleeds Abnormal menstrual bleeding Bleeding disorder risks include: Scarring of the joints or joint disease Vision loss from bleeding into the eye Chronic anemia from blood loss. Anemia is a low red blood cell count Neurologic or psychiatric problems Death, which may occur with large amounts of blood loss or bleeding in critical areas, such as the brain. 2 Not well understood: X-linked diseases with female bias •  Example: Neural tube closure defects •  Embryonic failure of the developing nervous system to close into a tube •  Is lethal or causes malformation of the brain Frog embryo shows neural plate Figure 20.9 Gastrulation in the Frog Embryo (Part 3) blue and green ectoderm to become part of the body--skin and brain Over the top to Neurulation Figure 20.15 form neural tube, in he Frog Embryo (Part tthefuture brain and spinal cord1) Neural plate folds up on edges and closes when the closure of the tube doesnt happen we have some problems normal neural tube closure defect Exencephaly growth of brain above and outside of skull Mouse embryo at 10 days Mouse model of neural tube defect Females more affected than males Two X chromosomes worse than one 18 day mouse embryos, day before birth With mutation that leads to neural tube closure failure in females 3 II. Autoimmune diseases Immune system attacks “self” proteins Sex differences in MS and other autoimmune diseases 4 characteristics of specific immune response 1. Specificity to antigens 2. Enormous scope of diversity 3. Ability to distinguish self from non-self 4. Immunological memory t he immune system can make antibodies o affect disiease millions and millions antibodies tell diff from your body to outside body leanrs not to atack your body cells mounts an immune sytem resonce to foreign molecule and you inject it and reponds with remembering it 1. Specificity antigenic determinants are parts of the antigen, specific parts of molecules that comprise the antigen antibodies are molecules that recognize and bind to antigen and remove it antigen this that is being atackedd 1. Specificity antigens are the foreign substances attacked by the immune system: cells, viruses, proteins, other foreign molecules antigenic determinants are parts of the antigen, specific parts of molecules that comprise the antigen antibodies are molecules that recognize and bind to antigen and remove it 4 2. Diversity Immune system can respond specifically to 10 million different antigenic determinants. 3. Distinguishing self from non-self Immune system does not generally attack body’s own antigens Exceptions: autoimmune diseases such as diabetes, multiple schlerosis, rheumatoid arthritis, myasthenia gravis, psoriasis, etc immune system does not attack it and is going ot learn it and when this goes wrong it is auto immune 4. Immunological memory Immune system remembers previously recognized antigens Biological basis of vaccination Multiple Sclerosis sclerosis = a hardening of a tissue or part MS is hardening of parts of the brain MS is an autoimmune disease that affects the central nervous system (brain, spinal cord, optic nerves). Surrounding and protecting the nerve fibers is a fatty tissue called myelin, which helps nerve fibers conduct electrical impulses. Immune system T cells enter brain and attack myelin proteins Myelin is lost in MS, leaving scars (sclerosis) or plaques or lesions. athero --outside becoming hard MS is a brain disease and attacks a specifi c brain nerves called the meylin f atty protien s heet 5 Variable MS symptoms Difficulty in walking Bladder or bowel dysfunction Dizziness and vertigo Depression or emotional changes Fatigue Numbness Pain Sexual dysfuntion Spasticity Vision problems Types of MS Relapse – Remitting (85% of cases) flare-ups, exacerbations, intermittent recovery Primary-Progressive (10%) slow, progressive continuous worsening Secondary-Progressive (50% of relapse-remitting) R-R, then slow progressive worsening Progressive – Relapsing (5%) slow progression with acute bad attacks Sex differences in MS Myelin Rich in protein and lipids Proteins include myelin basic protein (MBP) proteolipid protein (PLP) Females are 2-3 times more likely to get MS. Onset in females is earlier than in males. Onset usually age 20-50 More common in people of European ancestry but people with Asian and African ancestry also get MS. 400,000 Americans have MS. Average risk: 1/750 Risk if parent has MS: 1/40 Risk if identical twin has MS: 1/4 c orolation a>>b b>>a some factor c can cause both of them t he relation ship is there as the disease goes up testostreone goes down MS: Evidence for environmental factors Biological origins of the sex difference: Observations 1.  Female onset is typically after puberty, male onset typically in 30s and 40s 3.  MS symptoms are reduced during pregnancy 4.  MS may get worse after menopause. 5.  Oral contraceptives may improve MS symptoms. 6.  Pregnancy or contraceptives do not prevent MS. 7.  24% of male MS patients have lower testosterone levels than normal. 1. hormones could affect it the hormones tha go up at puberty to cause the disease more likley 2. pregnant women are not mentrating are infl enceing the disease 3. there are different but similar hormones affecting the s ex diff 7. testosterone prevents ms but is this enough information people who are born in canada but then moves to panama city 6 What can be concluded from these observations? 1.  Female onset is typically after puberty, male onset typically in 30s and 40s 3.  MS symptoms are reduced during pregnancy 4.  MS may get worse after menopause. 5.  Oral contraceptives may improve MS symptoms. 6.  Pregnancy or contraceptives do not prevent MS. 7.  24% of male MS patients have lower testosterone levels than normal. What experiments can be performed in humans to establish the biological origins of sex differences in MS? 1. Treat females or males with sex hormones? –  Estradiol, progesterone, testosterone? 2.  Remove gonads? 3. Observe differences in women who take oral contraceptives vs. those who do not? Differences pre- and post menopause? Differences in postmenopausal women who take hormones or not? 1. estrogen may affect them badly so it is unethetical if you get permission from patioent as ling as there are no long term trouble hat may affect them adly 2. cant do that experiment with humans 3. What experiments can be performed in humans to establish the biological origins of sex differences in MS? 4. Inject testosterone into pregnant women to make sure their male fetuses get enough testosterone? 5.  Compare CAH and normal females. 6.  Compare XXY vs. XY, XYY vs. XY 9.  Compare XO vs. XX Correlation vs. Causation 4. not thought to be ethical 9. ou can corrolate disease with genes but doesnt tell you the disease To determine biological origins, you need an animal model •  Animal models allow manipulation of causal factors, test causation •  Do the results from animal studies tell us anything about humans? Are they valuable, worthless, or what? •  Is it ethical to do experiments on animals? Is it legal? –  When yes and when no? EAE: Mouse model of MS Experimental autoimmune encephalomyelitis EAE: Mouse model of MS Experimental autoimmune encephalomyelitis 1.  Inject mouse with a myelin-related protein and induce an immune reaction to the protein (with an adjuvant). 2.  Mouse makes antibodies to the protein 3 5.  Mouse begins to show signs of weakness, inability to move, similar to MS. 3.  Mouse begins to show signs of weakness, inability to move, similar to MS. 4.  Females show progression of symptoms faster than males 5.  Which biological difference between males and females makes them different? 6.  What are the possibilities? What experiment would you do first? Adjuvant = agent that increases immunological response to antigen giving the mouse a disease it didnt have 7 EAE: inject mice with MBP myelin basic protein MBP! Measure severity of the disease Clinical score (5=bad, 0=good) Adoptive EAE: transfer lymph node cells from immunized mouse to recipient 1. immunize 2. Culture lymph node cells 3. Inject into recipient mouse 4. Measure clinical Score, high is bad, Low is good Compare two groups 1--tail goes 2. if you turn it over c an get over 3.hind legs dont work 4. 5. dead Adoptive EAE 1. Immunize male or female FEMALE MALE Adoptive EAE 1. Immunize mouse 2. Culture lymph node cells 3. Inject lymph node cells into recipient mouse, either male or female 4. Clinical score after transfer Into female mouse is worse than after transfer into male mouse MALE 2. Culture lymph node cells (immune system cells) 3. Inject cells into recipient mouse FEMALE MALE FEMALE FEMALE 4. Clinical score after transfer of female cells is worse than after transfer of male cells MALE 3 major classes of biological factors that cause sex differences What experiment to do first to test for the biological origins of the sex difference in EAE? 1. Activational effects of sex steroid hormones secreted by the gonads REVERSIBLE effects of hormones 2. Organizational effects of sex steroid hormones secreted by the gonads PERMANENT effects of hormones different history of hormone s ecretion 3.  Direct effects of sex chromosome genes Effects of Y genes in male cells Difference in effect of X genes in XX vs. XY cells. males in the room have y chromosome and females have 2 X 8 one sex Adoptive EAE 1. Immunize mouse 2. Culture lymph node cells First, test for activational effects •  1. Remove gonads of males and females to determine if gonadal secretions (activational effects) contribute to the sex difference. •  If gonadectomy abolishes sex difference, then treat males and females with identical levels of E, T or P to see which hormone influences the trait. MALE Castrated MALE Castrated MALE 3. Inject cells into recipient mouse, either male or castrated male 4. Clinical score worse in castrated male. What is the conclusion? MALE castrated male is worse off Adoptive EAE 1. Immunize mouse 2. Culture lymph node cells 3. Inject into recipient mouse, either male or castrated male 4. Clinical score worse in castrated male. Placebo FEMALE Adoptive EAE 1. Immunize mouse 2. Culture lymph node cells 3. Inject cells into recipient mouse, either placebo-treated female or DHT-treated female, DHT is an androgen MALE Castrated MALE Castrated MALE DHT FEMALE Placebo FEMALE MALE Conclusion: Testes protect from EAE. What are the possible hormones involved? 4. Clinical score worse in placebo-treated female DHT FEMALE Conclusion? DHT=dihydrotestosterone females treated wih dht are well protected Adoptive EAE 1. Immunize mouse Placebo FEMALE Adoptive EAE Placebo MALE 1. Immunize mouse 2. Culture lymph node cells Testosterone-treated MALE 2. Culture lymph node cells 3. Inject cells into recipient mouse, either placebo-treated female or DHT-treated female, DHT is an androgen 4. Clinical score worse in placebo-treated female DHT FEMALE DHT FEMALE Placebo FEMALE 3. Inject cells into recipient mouse, either placebo-treated male or testosterone-treated male, 4. Clinical score worse in placebo-treated male Placebo-treated MALE T-treated MALE Conclusion: Androgen protects from EAE in females 9 Adoptive EAE Placebo MALE Adoptive EAE: hormones of pregnancy 1. Immunize mouse 2. Culture lymph node cells FEMALES 1. Immunize mouse 2. Culture lymph node cells Testosterone-treated MALE 3. Inject cells into recipient mouse, either placebo-treated male or testosterone-treated male, 4. Clinical score worse in placebo-treated male Estriol Progesterone Placebo 3. Inject cells into recipient mouse, either placebo-treated female or estriol-treated male, or progesterone-treated female Placebo-treated MALE T-treated MALE Estriol 4. Clinical score best in estriol-treated female Conclusion: Testosterone protects from EAE in males Adoptive EAE: hormones of pregnancy 1. Immunize mouse 2. Culture lymph node cells FEMALES Estriol Weak estrogen secreted in the last part of pregnancy Good candidate for drug to treat women with MS Few side effects, natural molecule Now in clinical trials Animal research identifies candidate drug then tested in humans to alleviate disease Estriol Progesterone Placebo 3. Inject cells into recipient mouse, either placebo-treated female or estriol-treated male, or progesterone-treated female 4. Clinical score best in estriol -treated female Estriol Conclusion: Estriol estriol hormone protects from EAE in of pregnancy females estroil works better in alleviating the desease First test for activational effects •  1. Remove gonads of males and females to determine if gonadal secretions (activational effects) contribute to the sex difference. •  If gonadectomy abolishes sex difference, then treat males and females with identical levels of E, T or P to see which hormone influences the trait. 3 major classes of biological factors that cause sex differences 1. Activational effects of sex steroid hormones secreted by the gonads REVERSIBLE effects of hormones 2. Organizational effects of sex steroid hormones secreted by the gonads PERMANENT effects of hormones 3.  Direct effects of sex chromosome genes Effects of Y genes in male cells Difference in effect of X genes in XX vs. XY cells. 10 •  If gonadectomy does not abolish sex differences, then some other factor contributes to the sex difference, perhaps permanent masculinizing effects of testosterone in the fetus or neonate. •  Treat females with T at birth, or remove testosterone from males at birth, and test whether these treatments cause masculinization or demasculnization. Second, test for organizational effects of testosterone Third, test for sex chromosome effects •  Compare mice with different sex chromosomes which are hormonally equivalent, if possible. •  Compare XX vs XY females under identical hormonal conditions, for example. EAE: inject mice with MBP myelin basic protein MBP! Measure the cellular response to the autoimmunity Male gonad is immunosuppressive! Proliferation of lymph node cells ! 15000! 10000! 5000! 0! 20000 NUMBER ! * * !! ! * ! measure cell proliferation, cytokines XX XX XY XY Voskuhl lab, UCLA Testosterone is immunosuppressive, ! males are protected from immune response! by testosterone! EAE, mouse model of MS XX mice more susceptible than XY mice ! 15000! 10000! 5000! 0! 20000 NUMBER! Proliferation ! XX gonadectomized males XY gonadectomized males +T XY XY animals with a y chromosome are better off than x c hromosome 11 Summary: EAE 1.  Testosterone protects 2.  XX genome is worse than XY 3.  Estriol, hormone of pregnancy, protects New clinical trials treating women with weak estrogen estriol, to alleviate symptoms of MS Mouse model of disease gives new ideas for treatment of humans Politics and gender in research and medicine 1.  Male subjects are used much more often in research on humans and animals – WHY? 2.  Now a federal requirement to use both sexes in human research 3.  Are medical students taught to treat males and females differently? 4.  Are drugs developed that might be more effective in one sex than another? 5.  Is sex taken into account in the clinic? 12 ...
View Full Document

Ask a homework question - tutors are online